normal and abnormal puberty

PubertyPubertybyby

Dr. Hamdy AzabDr. Hamdy Azab

Ass. Prof. Cairo UniversityAss. Prof. Cairo University

PubertyPuberty

IntroductionIntroductionPuberty is defined as the period of time during whichPuberty is defined as the period of time during whichsecondary sexual characteristics develop, menstruationsecondary sexual characteristics develop, menstruationbegins and the psychological outlook of the girl changesbegins and the psychological outlook of the girl changes . .The end result of puberty is the establishment of the The end result of puberty is the establishment of the fullyfullyphysically mature adult woman capable of reproductivephysically mature adult woman capable of reproductiveperformance and fully psychologically developed as anperformance and fully psychologically developed as anadultadult..

Pubertal stagesPubertal stages

Normal puberty is a progression of events Normal puberty is a progression of events in both girls and boys that is generallyin both girls and boys that is generallycomplete in 3-4 years. In females, complete in 3-4 years. In females, thelarche (breast buds) is usually the first thelarche (breast buds) is usually the first sign of estrogen production and occurs at sign of estrogen production and occurs at an average age of 10.5 years, whilean average age of 10.5 years, whilepubarche (pubic hair growth) generally pubarche (pubic hair growth) generally occurs about 6 months later. In 10-20%occurs about 6 months later. In 10-20%of girls, pubarche is the first eventof girls, pubarche is the first event..


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

Physiology of pubertyPhysiology of puberty

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

Physiology of pubertyPhysiology 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 sexsteroids 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 pubertyPhysiology of pubertyLeptinLeptin has been proposed as the hormone responsible for the has been proposed as the hormone responsible for the initiation and progression of puberty. Leptin is produced initiation and progression of puberty. Leptin is produced largely in adipocytes; and serum leptin concentrations are largely in adipocytes; and serum leptin concentrations are highly correlated with body fat content. The potential highly correlated with body fat content. The potential importance of leptin is illustrated by the observation that importance of leptin is illustrated by the observation that mice and rats deficient in leptin fail to undergo pubertal mice and rats deficient in leptin fail to undergo pubertal development, whereas the administration of leptin to such development, whereas the administration of leptin to such animals results in pubertal onsetanimals results in pubertal onset . .

Leptin appears to be one of several factors that influence the Leptin appears to be one of several factors that influence the maturation of the gonadotropin-releasing hormone (GnRH) maturation of the gonadotropin-releasing hormone (GnRH) pulse generator, probably as a signal of the availability of pulse generator, probably as a signal of the availability of metabolic fuelmetabolic fuel..GPR54 geneGPR54 gene — The GPR54 gene on chromosome 19p13.3, — The GPR54 gene on chromosome 19p13.3, which encodes a Gwhich encodes a G--protein coupled receptor, appears to have protein coupled receptor, appears to have an important role in the initiation of puberty via its effect on an important role in the initiation of puberty via its effect on hypothalamic GnRHhypothalamic GnRH. . Mutations in GPR54 cause autosomal Mutations in GPR54 cause autosomal recessive idiopathic hypogonadotropic hypogonadism in recessive idiopathic hypogonadotropic hypogonadism in humans and in a GPR54 knockout mouse modelhumans and in a GPR54 knockout mouse model..

Precocious pubertyPrecocious puberty

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

ClassificationClassification

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

Central (True) precocious Central (True) precocious pubertypuberty

IdiopathicIdiopathic; 80-90% of cases; 80-90% of casesCNS tumorsCNS tumors, most commonly hamartomas, most commonly hamartomasCNS radiationCNS radiationOther CNS lesionsOther CNS lesions, such as hydrocephalus, cysts, trauma or , such as hydrocephalus, cysts, trauma or infection, empty sella syndromeinfection, empty sella syndromeGeneticsGenetics — GPR54 is a G protein-coupled receptor which acts — GPR54 is a G protein-coupled receptor which acts as a ligand for kisspeptin. The action of the kisspeptin-as a ligand for kisspeptin. The action of the kisspeptin-GPR54 signaling complex is essential for gonadotropin-GPR54 signaling complex is essential for gonadotropin-releasing hormone physiology and for initiation of puberty. releasing hormone physiology and for initiation of puberty. Gain-of-function mutations in GPR54 can cause central Gain-of-function mutations in GPR54 can cause central precocious puberty. Conversely, loss-of function mutations precocious puberty. Conversely, loss-of function mutations in GPR54 can cause hypogonadotropic hypogonadismin GPR54 can cause hypogonadotropic hypogonadism..Primary hypothyroidismPrimary hypothyroidism; rarely in longstanding cases due ; rarely in longstanding cases due to stimulation of FSH receptors by high TSHto stimulation of FSH receptors by high TSH..

Peripheral Precocious Puberty Peripheral Precocious Puberty (Gonadotropin-Independent)(Gonadotropin-Independent)

Ovarian cysts — Follicular cysts of the ovaries is the most Ovarian cysts — Follicular cysts of the ovaries is the most common cause of independent precocity in girls. Affected common cause of independent precocity in girls. Affected patients often present after an episode of vaginal bleedingpatients often present after an episode of vaginal bleeding..Ovarian tumors — Granulosa-cell tumors, Leydig cell tumors Ovarian tumors — Granulosa-cell tumors, Leydig cell tumors and gonadoblastoma are rare causes of precocious pubertyand gonadoblastoma are rare causes of precocious puberty..

Gonadotropins/HCG producing tumors- choriocarcionoma, Gonadotropins/HCG producing tumors- choriocarcionoma, dysgerminoma, teratomadysgerminoma, teratomaAdrenal pathology- CAH- There are a variety of types. These Adrenal pathology- CAH- There are a variety of types. These are autosomal recessive disorders of adrenal are autosomal recessive disorders of adrenal steroidogenesis leading to excess (ACTH), hence excess steroidogenesis leading to excess (ACTH), hence excess cortisol precursors which get pushed into the androgen cortisol precursors which get pushed into the androgen pathway leading to androgen excesspathway leading to androgen excess . .

Exogenous estrogen — Feminization has been attributed to Exogenous estrogen — Feminization has been attributed to excess estrogen exposure from creams and ointment, and excess estrogen exposure from creams and ointment, and food contaminationfood contamination..

Peripheral Precocious Puberty Peripheral Precocious Puberty (Gonadotropin-Independent)(Gonadotropin-Independent)

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

EvaluationEvaluation

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

Treatment of central Treatment of central precocious pubertyprecocious puberty

Decision to treat — The decision to treat central precocious puberty Decision to treat — The decision to treat central precocious puberty depends on the etiology and the pace of the sexual maturation. depends on the etiology and the pace of the sexual maturation. When there is an identifiable CNS lesions, therapy is directed, if When there is an identifiable CNS lesions, therapy is directed, if possible, toward the underlying pathology. If there is not an possible, toward the underlying pathology. If there is not an identifiable cause, the decision whether to treat is dependent on identifiable cause, the decision whether to treat is dependent on the rate of sexual maturation and the estimated adult heightthe rate of sexual maturation and the estimated adult height . .

Children who present very young and have a rapid progress of Children who present very young and have a rapid progress of maturation will have epiphyseal fusion at an early age. They will maturation will have epiphyseal fusion at an early age. They will attain the smallest adult height and therefore, benefit most from attain the smallest adult height and therefore, benefit most from therapytherapy . .

Children with central precocious puberty who are already close to the Children with central precocious puberty who are already close to the age of normal puberty or who have a very slowly progressive age of normal puberty or who have a very slowly progressive variant of precocious puberty may not require treatment at allvariant of precocious puberty may not require treatment at all..GnRH agonist therapyGnRH agonist therapy has become the standard for children with has become the standard for children with centralcentralprecocious puberty. The depot form of leuprolide acetate is given at a precocious puberty. The depot form of leuprolide acetate is given at a dose of 300 μg/kg every four weeksdose of 300 μg/kg every four weeks..

peripheral precocious peripheral precocious pubertypuberty

Children with tumors of the testis, adrenal gland, Children with tumors of the testis, adrenal gland, and ovary are treated by surgery. Those with hCG-and ovary are treated by surgery. Those with hCG-secreting tumors may require some combination secreting tumors may require some combination of surgery, radiation therapy, and chemotherapy of surgery, radiation therapy, and chemotherapy depending upon the site and histologic typedepending upon the site and histologic type . .

Children with obvious defects in adrenal Children with obvious defects in adrenal steroidogenesis should be treated with steroidogenesis should be treated with glucocorticoid therapyglucocorticoid therapy..

McCune-Albright syndrome — In girls with MAS, McCune-Albright syndrome — In girls with MAS, testolactone, which inhibits aromatization of testolactone, which inhibits aromatization of androgen to estrogen, has been at least partially androgen to estrogen, has been at least partially successful in decreasing the recurrence of ovarian successful in decreasing the recurrence of ovarian cysts, thereby slowing pubertal progressioncysts, thereby slowing pubertal progression . .

Delayed pubertyDelayed puberty

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


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.

EtiologyEtiology

Constitutional delayConstitutional delay of puberty in 70 of puberty in 70 percent of subjectspercent of subjects..

Permanent hypogonadotropic Permanent hypogonadotropic hypogonadismhypogonadism in 12 percent in 12 percent..

Permanent hypergonadotropic Permanent hypergonadotropic hypogonadismhypogonadism ((ie, primary gonadal ie, primary gonadal failurefailure) ) in 13 percentin 13 percent

UnclassifiedUnclassified, 5 percent, 5 percent

EvaluationEvaluationHistory — The history helps determine whether pubertal History — The history helps determine whether pubertal development is totally absent or had started but then development is totally absent or had started but then stalledstalled..Nutritional habits, exercise intensity, prior medical illness, or Nutritional habits, exercise intensity, prior medical illness, or medication usage should be analyzed. Delays in sexual medication usage should be analyzed. Delays in sexual maturation and growth velocity often can be the first maturation and growth velocity often can be the first clinical signs of underlying metabolic disorders, such as clinical signs of underlying metabolic disorders, such as inflammatory bowel disease, hypothyroidism, or inflammatory bowel disease, hypothyroidism, or psychosocial deprivationpsychosocial deprivation . .

The presence of associated congenital abnormalities (eg, The presence of associated congenital abnormalities (eg, midline defects), suggests congenital GnRH deficiency. midline defects), suggests congenital GnRH deficiency. Neurologic symptoms such as headache, visual Neurologic symptoms such as headache, visual disturbances, anosmia, dyskinesia, seizures, and mental disturbances, anosmia, dyskinesia, seizures, and mental retardation strongly suggest a central nervous system retardation strongly suggest a central nervous system disorderdisorder . .

A positive family history of either constitutional delay of A positive family history of either constitutional delay of puberty or congenital GnRH deficiency can be a useful cluepuberty or congenital GnRH deficiency can be a useful clue..


Physical examinationPhysical examinationBoth the standing height and the arm span Both the standing height and the arm span should be measured. An arm span should be measured. An arm span exceeding the height by more than 5 cm exceeding the height by more than 5 cm (ie, eunuchoidal body habitus) suggests (ie, eunuchoidal body habitus) suggests delayed epiphyseal closure secondary to delayed epiphyseal closure secondary to hypogonadismhypogonadism..Secondary sexual characteristics should be Secondary sexual characteristics should be staged according to the Tanner criteriastaged according to the Tanner criteria . .

Pelvic examination or imaging studies to Pelvic examination or imaging studies to evaluate internal organsevaluate internal organs..


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

Pure gonadal dysgenesis

Pure gonadal dysgenesisPure gonadal dysgenesis

Bilateral streak gonads are associated with Bilateral streak gonads are associated with aa

Normal karyotype (46 XX or 46 XY)Normal karyotype (46 XX or 46 XY)

Normal statureNormal stature

Primary amenorrheaPrimary amenorrhea

4646 XX pattern if associated with sensineural XX pattern if associated with sensineural deafness is known as Perrault deafness is known as Perrault syndromesyndrome..

4646 XY pattern is known as Swyer syndromeXY pattern is known as Swyer syndrome


THERAPY THERAPY — — If a specific underlying disorder can be If a specific underlying disorder can be identified, therapy should be targeted at that disorder. As identified, therapy should be targeted at that disorder. As examples, thyroid hormone replacement in hypothyroidism, examples, thyroid hormone replacement in hypothyroidism, dopamine agonist treatment of pituitary adenomas, and dopamine agonist treatment of pituitary adenomas, and excision of craniopharyngiomas can result in prompt excision of craniopharyngiomas can result in prompt institution of sexual maturationinstitution of sexual maturation . .

In most patients, however, the distinction between congenital In most patients, however, the distinction between congenital GnRH deficiency and constitutional delay of puberty GnRH deficiency and constitutional delay of puberty remains uncertain, and can be resolved only with serial remains uncertain, and can be resolved only with serial observationsobservations..

In view of these diagnostic difficulties, the initial therapeutic In view of these diagnostic difficulties, the initial therapeutic approach is similar for both disorders. The two major approach is similar for both disorders. The two major options are "watchful waiting" with reassurance and options are "watchful waiting" with reassurance and psychological support for the patient and family or the psychological support for the patient and family or the administration of gonadal steroidsadministration of gonadal steroids . .


Short-term therapeutic goals include: Attainment of age-Short-term therapeutic goals include: Attainment of age-appropriate secondary sex characteristics to ameliorate the appropriate secondary sex characteristics to ameliorate the patient's concern about his/her appearance relative to patient's concern about his/her appearance relative to peerspeers..

Induction of a growth spurt without inducing premature Induction of a growth spurt without inducing premature epiphyseal closure. This goal requires frequent (eg, every epiphyseal closure. This goal requires frequent (eg, every six months) longitudinal monitoring of bone age during six months) longitudinal monitoring of bone age during therapytherapy..

The long-term goals of therapy, if the diagnosis proves to be The long-term goals of therapy, if the diagnosis proves to be isolated GnRH deficiency, are to maintain the serum isolated GnRH deficiency, are to maintain the serum concentrations of sex steroids within the normal adult concentrations of sex steroids within the normal adult range and, eventually, to induce fertility if and when the range and, eventually, to induce fertility if and when the patient desirespatient desires..


Estrogen therapy — In girls, estrogen can be given Estrogen therapy — In girls, estrogen can be given orally or transdermally, initially at doses well below orally or transdermally, initially at doses well below those used for replacement therapy in adults. A those used for replacement therapy in adults. A progestin should not be added until there is progestin should not be added until there is substantial breast development as premature substantial breast development as premature initiation of progestin therapy can compromise initiation of progestin therapy can compromise ultimate breast growthultimate breast growth..

Once breast growth has plateaued during serial Once breast growth has plateaued during serial evaluation and menstruation been established, evaluation and menstruation been established, estrogen therapy can be discontinued intermittently estrogen therapy can be discontinued intermittently for one- to three-month periods to determine if for one- to three-month periods to determine if spontaneous menstruation occurs, which should spontaneous menstruation occurs, which should happen in girls with constitutional delayhappen in girls with constitutional delay..

normal and abnormal puberty

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