Puberty: more than hormones
Puberty: more than hormones |
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Key words: puberty, genetics, environment, obesity, endocrinology.
Introduction
Puberty can be defined as a period of transition between childhood and adulthood. Parents know when puberty begins and they interpret behaviour changes to indicate hormonal fluxes. Paediatricians who care for the adolescent aged child also know when puberty begins as they carefully listen to the parents and their patients and perform physical examination to determine the way they describe physical changes which announce this stage of development. However, the most sophisticated paediatrician (endocrinologist) struggles to define the hormonal markers for puberty.
The transition from childhood to adulthood is controlled by complex neuro-endocrine factors responsible for its onset and progression into full sexual maturity. Biological changes that occur during puberty include several neuro-secretory factors and/or hormones. All these factors modulate somatic growth, the development of sex glands and their endocrine as well as exocrine secretions. The resultant increase in sex steroid production will ensure the appearance and maintenance of sexual characteristics and the capacity for reproduction. The entire endocrine system is altered during adolescence, and growth hormone, thyroid and adrenal hormones are all involved in this maturational process.
However, it is essentially the activation of the hypothalamic-pituitary-gonadal axis that induces and enhances the progressive ovarian and testicular sex hormone. Secretions that are responsible for the profound biological, morphological and psychological change to which the adolescent is subjected. The events of puberty are likely to be part of a strict genetically programme that seems to begin in early infancy and probably even during fetal life. Peak activity of the hypothalamic-pituitary-gonadal axis is also found during the first two trimesters of gestation and in early infancy and therefore not limited exclusively to adolescence 1.
In a study of the monkey Cebus Apella, testicular and seminiferous tubule volumes increased significantly in the first 5 months of life and during puberty2. Sertoli cells proliferated in the neonatal and infantile periods, determining a longitudinal growth of the seminiferous tubules, but remain stable during puberty, when androgen binding protein secretion increased significantly. The genetic programming regulates and modulates hypothalamic gonadotrophin-releasing hormone (GnRH), pituitary (gonadotrophin and prolactin) and gonadal (androgen and oestrogen) hormone secretions, and the biological action of sex steroids at the periphery through the induction and regulation of specific receptors. Several intrinsic and environmental factors may influence the timing of puberty. Chronic illness, psychological deprivation, sustained child abuse, prolonged psychological and physical stress including intensive competitive training and exercise may all delay puberty. Central nervous system disease may accelerate its onset.
Stages of puberty: there isn't adequate space for inclusion of the staging of puberty as this is readily available in standard text based on Tanner et al3. It is important however to recognise that for girls there is breast development and for boys increase in testicular volume as the two major differences. Pubic hair development is the same. Onset of menstruation, which is dependant on ovarian and uterine development as specific to girls and also require specific investigations in terms of ultrasound scan and hormonal assays.
Factors involved in puberty
Heredity, sickness, nutrition have an effect on the hypothalamus. Stress has an effect on the hypothalamus as well and involves neurotransmitters within the central nervous system (CNS). Leptin, the product of the OB gene, is an adipocyte-derived hormone that is thought to signal onset of puberty. Leptin signal the amount of adipose tissue energy stores to the brain and exerts major effects on energy homeostasis and neuro-endocrine function. It has been shown to affect reproductive function in leptin deficient and normal rodents. A longitudinal study on pre-pubertal boys followed up through to puberty showed a rise of leptin by 50% just before onset of puberty and decreased to approximately baseline values after the initiation of puberty4,5.
Body composition in particular fat mass, through leptin, is a critical signal to timing of the biological
clock of puberty. Thus nutritional status, for example anorexia nervosa, starvation or obesity is implicated. The former delays are puberty and the later accelerates puberty. The hypothalamic hormones GnRH, CRF have a positive effect on the anterior pituitary whilst prolactin-inhibiting factor (PIF) has a negative effect.
In turn, ACTH acts on the adrenal glands and LH, FSH act on the gonads to influence the release of sex steroids and subsequent development of puberty. Oestradiol and testosterone have different effects on inhibin and the hypothalamus. Adrenal androgens influence the timing of secondary sexual characteristics . Diurnal rhythms of LH, FSH and testosterone exist at 5-6 years of age. LH and testosterone levels increase before onset of puberty. In this study6, there is evidence therefore to suggest that preparation for the onset of female puberty will begin in 5 -6 year old girls. The increase in obesity may accelerate this phenomenon. In our clinical practice as highlighted below we are seeing girls referred to us with high body mass index and early puberty.
There are other factors that need further investigation to determine modulation of the timing of puberty7,8,9 . The timing of puberty follows a normal distribution curve. 2.5 standard deviations below the mean constitutes precocious puberty where females predominate and 2.5 standard deviations above the mean, which is predominantly male, constitute delayed puberty. The determination of what constitutes normal puberty may therefore be arbitrary. The international migration, dietary changes and stress factors are all influencing this statistical timing. Thus for a cosmopolitan population the age of onset of puberty may vary depending on the genetic background as well as nutritional status. The changes in the American population show that 27% of African American girls and 7% of white girls show some secondary sexual characteristics by the age of 7 years7. The working definition of precocious puberty is 8 years for girls. This therefore creates a problem for the clinicians in deciding whether to investigate an individual child. In clinical practice therefore the family history, the history of the pubertal signs and symptoms are critical in enabling the paediatrician to decide whether or not to investigate. When puberty in a young child GnRH dependant this is classified as central precocious puberty (CPP). Such children experience development of secondary sexual characteristics. This is associated with accelerated linear growth and progressive advanced bone age. Sex hormones and gonadotrophins will be in the pubertal levels. At the moment, it is very difficult to differentiate between pre-pubertal and pubertal LH levels, as most sensitive immuno assays are not readily available. GnRH stimulation test, LH response is very dramatic in CPP and tends to be 2-3 fold higher than the pre-pubertal levels and exceeds the relative rise of FSH. There is a slight difference in those with slowly progressive CPP and sometimes described by others as ‘early slow puberty’. Comparative information on linear growth, hormone levels and bone age development is slower. Idiopathic CPP is common in girls. Other association includes CNS lesion (hypothalamic haematoma, neurofibromatosis, hydrocephalus, CNS infection and intracranial neoplasm and CNS irradiation). In this group of patients the female to male ration is about the same. In our practice all these patients have been seen over the past 10 years, but ICCP constitutes the majority of our patients including several families with two siblings. However there are more children being referred with early slow progressing puberty. The increase in the number of such children seems to mirror the increase in obesity. Over the past 10 years, the prevalence of obesity has increased from 3% to 10 % for age groups between 6-15 years of age. Most of these children have shown elevated levels of adrenal androgens, advanced bone age, slight elevation of LH and a minimal rise of FSH following GnRH stimulation.
Delayed puberty is failure to have manifest signs of sexual maturation by an age that is more than 2.5 standard deviation above the mean for the population. This is currently believed to be 13 years for girls and 14 years for boys. Our clinical experience shows that these are mostly boys with delayed puberty who have no underlying pathological problem. There is however a genetic component as in as many as 85% adolescent there is a family history of constitutional delay of growth and development of puberty (CDG & P). The bone age is delayed and on GnRH stimulation test the gonadotrophin levels are pre-pubertal. In those patients with pathological disorders, CNS, gastrointestinal or other systemic illnesses the sex ratio is equal. In summary therefore for CPP and CDG & P there is a strong genetic predisposition. There are conditions where genetics plays a bigger role and this has been described within the past 10 years. These include hypothalamic hypogonadism, x-linked Kallmann's syndrome, androgen insensitivity and GnRH receptor. There are other conditions like congenital adrenal hypoplasia. The actual mechanisms include combinations of disorders, for example GnRH processing resulting into hypogonadic hypogonadism and obesity. Failure of pubertal maturation by impinging directly on GnRH activity through disruption of neuronal migration (KAL), hypothalamic pituitary development (DAX1), GnRH processing (PC1), or its signalling (GnRH). Most of these conditions are very rare but clearly elucidate the genetic influence. Of course there are the common chromosome disorders that have been well defined, including Klinefelter and Turner's syndromes.
Premature thelarche or premature development of the breasts:
Premature pubarche or premature adrenarche is the precocious development of pubic and axillary hair due to maturation of the androgen secretion of the adrenal cortex and/or to premature change in sensitivity to androgens of the target tissue receptors. Mostly seen at six years of age and more common in girls.
Premature development of breasts is usually seen between the age of one and three years. Signs of oestrogenisation are always absent and there is no sexual hair. Pubertal gynaecomastia is the development of breast during male puberty. The commonest cause is idiopathic and occurs in about 30% to 65% of the boys.
In summary, puberty is a complex transitional period primarily determined by genetics and therefore follows familial pattern. It can be influenced by germ cell mutations, environmental factors and results in changes that influence growth, development and behaviour. Parents and clinicians need to recognise the complexity of the problem. More understanding of the various factors that affect puberty will ensure better timing of interventions that can be helpful in some of the children. This is especially so in those with either precocious puberty or absent puberty. The increase in obesity among children is influencing the timing of puberty and it may be necessary to obtain normative data for our population to ensure that many children are not investigated unnecessarily.
References:
1. Ducharme JR. Normal puberty: clinical manifestations and their endocrine control. In: Collu R, Ducharme JR, Guyda H Eds. Paediatric endocrinology.2nd Ed. New York: Raven Press, 1989:307-330
2. Rey RA, Campo SM, Bedecarras P, Nagle CA and Chemes HE. J Clin Endocrinol Metabol 1993; 76:1325-1331
3. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height weight height velocity, weight velocity and stages of puberty. Arch Dis Child 1976; 51:170-179
4. 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 Metabol 1997; 82: 1066-1070.
5. Quinton ND, Smith RF, Clayton PE et al. Leptin Binding Activity changes with Age: The Link between Leptin and Puberty. J Clin Endocrinol Metabol 199; 84:2336-2341.
6. Mitamura R, Yano K, Suzuki N, Ito Y, Nakita Y, Okuno A. Diurnal Rhythms of Luteinizing hormone, Follicle Stimulating Hormone, Testosterone, and Estradiol secretion before onset of Female Puberty in Short children. J Clin Endocrinol Metabol 2000; 85: 1074-1080
7. Palmert MR, Boepple PA. Variation in the timing of Puberty: Clinical spectrum and Genetic Investigation. J Clin Endocrinol Metabol 2001; 86: 2364-2368
8. 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 Metabol 1997; 82: 2849-2855
8. Ahmed ML, Ong KK, Morrecc DJ et al. Longitudinal study of Leptin concentrations during Puberty: Sex differences and Relationship to Changes in Body Composition. J Clin Endocrinol Metabol 1999; 84:899-905
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