Delayed puberty

Puberty is considered delayed when the child has not begun puberty when two standard deviations or about 95% of children from similar backgrounds have. In North American girls, puberty is considered delayed when breast development has not begun by age 13, when they have not started menstruating by age 15, The age of onset of puberty is dependent on genetics, general health, socioeconomic status, and environmental exposures. Children residing closer to the equator, at lower altitudes, in cities and other urban areas generally begin the process of puberty earlier than their counterparts. Mildly obese to morbidly obese children are also more likely to begin puberty earlier than children of normal weight. Variations in genes related to obesity, such as FTO or NEGRI, have been associated with earlier onset of puberty. Children whose parents started puberty at an earlier age were also more likely to experience it themselves, especially in women where onset of menstruation correlated well between mothers and daughters and between sisters. ==Causes==

Pubertal delay can be separated into four categories from most to least common: These children have a history of shorter stature than their age-matched peers throughout childhood, but their height is appropriate for bone age, meaning that they have delayed skeletal maturation with potential for future growth. It is often difficult to establish if it is a true constitutional delay of growth and puberty or if there is an underlying pathology because lab tests are not always discriminatory. In the absence of any other symptoms, short stature, delayed growth in height and weight, and/or delayed puberty may be the only clinical manifestations of certain chronic diseases including coeliac disease. Malnutrition or chronic disease When underweight or sickly children are present with pubertal delay, it is warranted to search for illnesses that cause a temporary and reversible delay in puberty. and thalassemia, cystic fibrosis, HIV/AIDS, hypothyroidism, chronic kidney disease, and chronic gastroenteric disorders (such as coeliac disease and inflammatory bowel disease) cause a delayed activation of the hypothalamic region of the brain to send signals to start puberty. Childhood cancer survivors can also present with delayed puberty secondary to their cancer treatments, especially males. The type of treatment, amount of exposure/dosage of drugs, and age during treatment determine the level by which the gonads are affected, with younger patients at a lower risk of negative reproductive effects. Eating disorders such as bulimia nervosa and anorexia nervosa can also impair puberty due to undernutrition. Carbohydrate-restricted diets for weight loss have also been shown to decrease the stimulation of insulin which in turn does not stimulate kisspeptin neurons, vital in the release of puberty-starting hormones. This shows that carbohydrate restricted children and children with diabetes mellitus type 1 can have delayed puberty. Primary failure of the ovaries or testes (hypergonadotropic hypogonadism) Primary failure of the ovaries or testes (gonads) will cause delayed puberty due to the lack of hormonal response by the final receptors of the HPG axis. Congenital disorders Congenital diseases include untreated cryptorchidism where the testicles fail to descend from the abdomen. defects in the production of testicular steroids, receptor mutations preventing testicular hormones from working, chromosomal abnormalities such as Noonan syndrome, or problems with the cells making up the testes. The HPG axis can be altered in two places, at the hypothalamic or at the pituitary level. CNS disorders such as childhood brain tumors (e.g. craniopharyngioma, prolactinoma, germinoma, glioma) can disrupt the communication between the hypothalamus and the pituitary. Pituitary tumors, especially prolactinomas, can increase the level of dopamine causing an inhibiting effect to the HPG axis. Hypothalamic disorders include Prader-Willi syndrome and Kallmann syndrome, but the most common cause of hypogonadotropic hypogonadism is a functional deficiency in the hormone regulator produced by the hypothalamus, the gonadotropin-releasing hormone or GnRH. ==Diagnosis==

Pediatric endocrinologists are the physicians with the most training and experience in evaluating delayed puberty. A complete medical history, review of systems, growth pattern, and physical examination, as well as laboratory testing and imaging, will reveal most of the systemic diseases and conditions capable of arresting development or delaying puberty, as well as providing clues to some of the recognizable syndromes affecting the reproductive system. History and physical Constitutional and physiologic delay Children with constitutional delay are reported to be shorter than their peers, lacking a growth spurt, and having an overall smaller build. Deficiencies in GnRH, the signalling hormone produced by the hypothalamus, can cause congenital malformations including cleft lip and scoliosis. It is often sufficient to simply measure the baseline gonadotrophin levels to differentiate between the two. In girls with hypogonadotropic hypogonadism, a serum prolactin level is measured to identify if they have the pituitary tumor prolactinoma. High levels of prolactin would warrant further testing with MRI imaging, except if drugs inducing the production of prolactin can be identified. If the child has any neurological symptoms, it is highly recommended that the physician obtains a head MRI to detect possible brain lesions. In girls with hypergonadotropic hypogonadism, a karyotype can identify chromosomal abnormalities, the most common of which is Turner syndrome. In boys, a karyotype is indicated if the child may have a congenital gonadal defect such as Klinefelter syndrome. In children with a normal karyotype, defects in the synthesis of the adrenal steroid sex hormones can be identified by measuring 17-hydroxylase, an important enzyme involved in the production of sex hormones. ==Management==

The goals of short-term hormone therapy are to induce the beginning of sexual development and induce a growth spurt, but it should be limited to children with severe distress or anxiety secondary to their delayed puberty. Girls can be started on estrogen with the same goals as their male counterparts. Malnutrition or chronic disease If the delay is due to systemic disease or malnutrition, the therapeutic intervention is likely to focus direction on those conditions. In patients with coeliac disease, an early diagnosis and the establishment of a gluten-free diet prevents long-term complications and allows restoration of normal maturation. Choice of formulation (topical vs injection) is dependent on the child's and family's preference as well as on how well they tolerate side effects. such as idiopathic short stature. More therapies are being developed to target the more discreet modulators of the HPG axis including kisspeptin and neurokinin B. In cases of severe delayed puberty secondary to hypogonadism, evaluation by a psychologist or psychiatrist, as well as counseling and a supportive environment are an important supplemental therapy for the child. Transition from pediatric to adult care is also vital as many children are lost during transition of care. == Outlook ==

Constitutional delay of growth and puberty is a variation of normal development with no long-term health consequences, however it can have lasting psychological effects. Adolescent boys with delayed puberty have a higher level of anxiety and depression relative to their peers. Children with delayed puberty also display decreased academic performance in their adolescent education, but changes in academic achievement in adulthood have not been determined. However, some studies show that these children fall short of their target height from about 4 to 11 cm. Men with delayed puberty often have low to normal bone mineral density unaffected by androgen therapy. Women are more likely to have lower bone mineral density and thus an increased risk of fractures as early as even before the onset of puberty. Furthermore, delayed puberty is correlated with a higher risk in cardiovascular and metabolic disorders in women only, but also appears to be protective for breast and endometrial in women and testicular cancer in men. == See also ==