Normal And Abnormal Puberty

Puberty by Dr. Hamdy Azab Ass. Prof. Cairo University

Puberty Introduction Puberty is defined as the period of time during which secondary sexual characteristics develop, menstruation begins and the psychological outlook of the girl .changes The end result of puberty is the establishment of the fully physically mature adult woman capable of reproductive performance and fully psychologically developed as an .adult

Pubertal stages Normal puberty is a progression of events in both girls and boys that is generally complete in 3-4 years. In females, thelarche (breast buds) is usually the first sign of estrogen production and occurs at an average age of 10.5 years, while pubarche (pubic hair growth) generally occurs about 6 months later. In 1020%

Pubertal stages

Pubertal stages Maximal growth velocity occurs in girls at age 12 and usually results in about a 9 cm increase in .height Menarche (initiation of menses) occurs on the downward arm of the growth curve at a median age of 12.5 years (white: 12.6 years; black: 12.15 /years; Mexican American: 12.3 years). A variety of additional factors affect pubertal onset, such as weight, stress, and extreme physical activity. Some authors have noted a younger age of onset of breast development and possibly menarche in African-American girls that may be .attributable to a greater BMI

Physiology of puberty The onset of puberty is controlled by many factors that remain incompletely understood. The overall earlier onset of puberty among the general population has been attributed to the increasing prevalence of obesity. It has been proposed that a critical body weight or body composition is the most salient issue in the development and maintenance of pubertal events. However, body weight alone probably is not a sufficient .explanation

Physiology of puberty It appears that the hypothalamic–pituitary– gonadal axis in girls develops in two .distinct stages during puberty First, sensitivity to the negative or inhibitory effects of the low levels of circulating sex steroids present in childhood decreases .early in puberty Second, late in puberty, there is maturation of the positive or stimulatory feedback response to estrogen, which is responsible .for the ovulatory midcycle surge of LH

Physiology of puberty Leptin has been proposed as the hormone responsible for the initiation and progression of puberty. Leptin is produced largely in adipocytes; and serum leptin concentrations are highly correlated with body fat content. The potential importance of leptin is illustrated by the observation that mice and rats deficient in leptin fail to undergo pubertal development, whereas the administration of leptin to such .animals results in pubertal onset Leptin appears to be one of several factors that influence the maturation of the gonadotropin-releasing hormone (GnRH) pulse generator, probably as a signal of the availability of .metabolic fuel GPR54 gene — The GPR54 gene on chromosome 19p13.3, which encodes a G-protein coupled receptor, appears to have an important role in the initiation of puberty via its effect on hypothalamic GnRH .Mutations in GPR54 cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and in a GPR54 knockout mouse .model

Precocious puberty DEFINITION — Abnormal or precocious early pubertal development is defined as children entering puberty more than 2.5 standard deviations (SD) earlier than the median or mean .age Based upon this definition and the assumption that the average age of onset of puberty was 10 years in girls and 12 years of age in boys,precocious puberty had been defined as secondary sexual development before the age of 8 years in girls and 9 years in boys N.B. This disorder is five times more common in .girls than boys

Classification Central precocious puberty is characterized in girls by both breast and pubic hair sexual maturation. It is caused by earlier activation of the normal pubertal developmental process mediated by the HPG axis. In these patients, the sexual characteristics are appropriate for the .(child's gender (isosexual Peripheral precocious puberty, is caused by an autonomous peripheral excess sex hormones (eg, estradiol and testosterone), which is independent of the HPG axis. In these patients, it is further .classified to isosexual or contrasexual

Central (True) precocious puberty Idiopathic; 80-90% of cases CNS tumors, most commonly hamartomas CNS radiation Other CNS lesions, such as hydrocephalus, cysts, trauma or infection, empty sella syndrome Genetics — GPR54 is a G protein-coupled receptor which acts as a ligand for kisspeptin. The action of the kisspeptinGPR54 signaling complex is essential for gonadotropinreleasing hormone physiology and for initiation of puberty. Gain-of-function mutations in GPR54 can cause central precocious puberty. Conversely, loss-of function mutations .in GPR54 can cause hypogonadotropic hypogonadism Primary hypothyroidism; rarely in longstanding cases due .to stimulation of FSH receptors by high TSH

Peripheral Precocious Puberty ((Gonadotropin-Independent Ovarian cysts — Follicular cysts of the ovaries is the most common cause of independent precocity in girls. Affected .patients often present after an episode of vaginal bleeding Ovarian tumors — Granulosa-cell tumors, Leydig cell tumors .and gonadoblastoma are rare causes of precocious puberty Gonadotropins/HCG producing tumors- choriocarcionoma,  dysgerminoma, teratoma Adrenal pathology- CAH- There are a variety of types. These are autosomal recessive disorders of adrenal steroidogenesis leading to excess (ACTH), hence excess cortisol precursors which get pushed into the androgen .pathway leading to androgen excess Exogenous estrogen — Feminization has been attributed to excess estrogen exposure from creams and ointment, and .food contamination

Peripheral Precocious Puberty ((Gonadotropin-Independent McCune-Albright syndrome — (MAS) is a rare disorder defined as the triad of peripheral precocious puberty, café-au-lait skin pigmentation, and fibrous dysplasia of .bone Patients with MAS have a somatic mutation of the alpha subunit of the G3 protein that activities adenylate cyclase. This mutation leads to continued stimulation of endocrine function (eg, precocious puberty, gigantism, Cushing syndrome, adrenal hyperplasia, and thyrotoxicosis), .in various combintations

Evaluation Basal LH levels and GnRH stimulation — Children with central precocious puberty can be distinguished from those with peripheral precocious puberty on the basis of measurements of LH levels, at baseline and after administration of GnRH. In peripheral PP, LH and FSH levels are low at baseline and will not increase with GnRH stimulation. In a central process, basal levels of LH and FSH are often at pubertal levels and will .increase with GnRH stimulation

Treatment of central precocious puberty Decision to treat — The decision to treat central precocious puberty depends on the etiology and the pace of the sexual maturation. When there is an identifiable CNS lesions, therapy is directed, if possible, toward the underlying pathology. If there is not an identifiable cause, the decision whether to treat is dependent on .the rate of sexual maturation and the estimated adult height Children who present very young and have a rapid progress of maturation will have epiphyseal fusion at an early age. They will attain the smallest adult height and therefore, benefit most from .therapy Children with central precocious puberty who are already close to the age of normal puberty or who have a very slowly progressive .variant of precocious puberty may not require treatment at all GnRH agonist therapy has become the standard for children with central precocious puberty. The depot form of leuprolide acetate is given at a .dose of 300 μg/kg every four weeks

peripheral precocious  puberty Children with tumors of the testis, adrenal gland, and ovary are treated by surgery. Those with hCG-secreting tumors may require some combination of surgery, radiation therapy, and chemotherapy depending upon the site and .histologic type Children with obvious defects in adrenal steroidogenesis should be treated with .glucocorticoid therapy McCune-Albright syndrome — In girls with MAS, testolactone, which inhibits aromatization of androgen to estrogen, has been at least partially successful in decreasing the recurrence of ovarian cysts, thereby slowing pubertal .progression

Delayed puberty INTRODUCTION — Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics bounded by an age at which 95 percent of children of that sex and culture have initiated sexual .maturation

Delayed puberty Delayed or interrupted puberty exists in girls who fail to develop any secondary sex characteristics by age 13, have not had menarche by age 16, or have not attained menarche 5 or more years since the onset of .pubertal development

Etiology Constitutional delay of puberty in 70 .percent of subjects Permanent hypogonadotropic hypogonadism. in 12 percent Permanent hypergonadotropic hypogonadism (ie, primary gonadal failure )in 13 percent Unclassified, 5 percent

Evaluation History — The history helps determine whether pubertal development is totally absent or had started but then .stalled Nutritional habits, exercise intensity, prior medical illness, or medication usage should be analyzed. Delays in sexual maturation and growth velocity often can be the first clinical signs of underlying metabolic disorders, such as inflammatory bowel disease, hypothyroidism, or .psychosocial deprivation The presence of associated congenital abnormalities (eg, midline defects), suggests congenital GnRH deficiency. Neurologic symptoms such as headache, visual disturbances, anosmia, dyskinesia, seizures, and mental retardation strongly suggest a central nervous system .disorder A positive family history of either constitutional delay of .puberty or congenital GnRH deficiency can be a useful clue

Evaluation Physical examination Both the standing height and the arm span should be measured. An arm span exceeding the height by more than 5 cm (ie, eunuchoidal body habitus) suggests delayed epiphyseal closure secondary to .hypogonadism Secondary sexual characteristics should be .staged according to the Tanner criteria Pelvic examination or imaging studies to  .evaluate internal organs

Evaluation Imaging studies A conventional X-ray of the left hand and wrist to evaluate bone age may be obtained at the initial visit to assess skeletal maturation and repeated .over time if needed Pelvic or testicular ultrasonography should be performed when an ovarian or testicular mass is detected on the physical examination Pelvic ultrasound also may be performed in girls with delayed puberty to determine the presence .or absence of a uterus Head MRI should be ordered if associated neurologic symptoms or signs suggest a central process, or if the laboratory studies are .consistent with hypothalamic or pituitary disease

Pure gonadal dysgenesis

Pure gonadal dysgenesis Bilateral streak gonads are associated with a (Normal karyotype (46 XX or 46 XY Normal stature Primary amenorrhea XX pattern if associated with 46 sensineural deafness is known as .Perrault syndrome XY pattern is known as Swyer 46

Delayed puberty THERAPY — If a specific underlying disorder can be

identified, therapy should be targeted at that disorder. As examples, thyroid hormone replacement in hypothyroidism, dopamine agonist treatment of pituitary adenomas, and excision of craniopharyngiomas can result in prompt .institution of sexual maturation In most patients, however, the distinction between congenital GnRH deficiency and constitutional delay of puberty remains uncertain, and can be resolved only with serial .observations In view of these diagnostic difficulties, the initial therapeutic approach is similar for both disorders. The two major options are "watchful waiting" with reassurance and psychological support for the patient and family or the .administration of gonadal steroids

Delayed puberty Short-term therapeutic goals include: Attainment of ageappropriate secondary sex characteristics to ameliorate the patient's concern about his/her appearance relative to .peers Induction of a growth spurt without inducing premature epiphyseal closure. This goal requires frequent (eg, every six months) longitudinal monitoring of bone age during .therapy The long-term goals of therapy, if the diagnosis proves to be isolated GnRH deficiency, are to maintain the serum concentrations of sex steroids within the normal adult range and, eventually, to induce fertility if and when the patient .desires

Delayed puberty Estrogen therapy — In girls, estrogen can be given orally or transdermally, initially at doses well below those used for replacement therapy in adults. A progestin should not be added until there is substantial breast development as premature initiation of progestin therapy can .compromise ultimate breast growth Once breast growth has plateaued during serial evaluation and menstruation been established, estrogen therapy can be discontinued intermittently for one- to three-month periods to determine if spontaneous menstruation occurs, which should happen in girls with constitutional .delay