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Home , Gonadarche, Premature thelarche

PRECOCIUS

Agnieszka Krosnowska Normal pubertal development

● Puberty is a proces through which reproductive competence is achived and is initiated by reactivation of the hypothalamic-pituitary-gonadal axis (gonadarche). ● Adrenal puberty maturation is indicated by increased adrenal dehydroepiandrosterone sulfate (DHEAS) secretion, occurs on close temporal proximity to gonadarche. Clinical studies have demostrated that gonadarche and are regulated through different molecular mechanisms. ● The typical sequence of puberty events for boys and girls is generally predictable. For both boys and girls, mean ages for the oneset of puberty vary among different ethnic groups and represent the combined influences of genetic and environmental factors. ● In BOYS, pubery first is evidenced by testicular enlargement, which usually begins between 9 and 14 years old. ● In GIRLS, puberty, evidenced is by development, which usually begins between 8 and 12 years old. Among white girls, the mean age of oneset of and pubic hair growth occurs at approximately 10 years old, with occuring at approximately 12 to 12 and a half years old. ● For girls, increased BMI may be associated with premature adrenarche and earlier pubertal onset. ● Large-scale population studies and have identified a secular trend for slightly earlier ( by 2 and a half to 4 months) ages at menarche throughtout the early 20th century. ● Boys with rapid weight gain during childchood tend to have a later onset of puberty. Tanner Staging

● To describe the onset and progression of pubertal changes boys and girls are rated no five-point scales. ● GIRLS- breast development, pubic hair growth ● BOYS- genital development, pubic hair growth

Physiology

Perinatal Period an Infancy

● Maternal stimulate breast development in both male and female fetuses. Maternal estrogens also stimulate uterine developmental and endometrial growth; at birth , withdrawal of the high levels of maternal and placental progesterone causes the infant endometrium to regress or even slough and manifests as vaginal bleeding. ● At birth, levels of LH and FSH in both sexes rise markedly and remain elevated for several months. In the girls, FSH stimulates ovarian granulosa cells to produce 17B- sufficient to maintain prenatal breast development for up to 8 month of life ● Male breast development regresses rather quickly after birth. Eleveted LH levels after birth stimulate Leydig cell production of for 6-12 months, leading to further genital development. Childchood

● By 2 years of age, serum levels decrease, and thus serum sex steroid levels also decrease, frequently to levels undetectable by conventional assays. ● Beginning approximentaly at ages 6-7 years in female and 7-8 in males, adrenal androgen production begins to increase and can be detect by the presece of increasing concentrationof the weak adrenal androgen dehydroepiandrosterone (DHEA) and DHEA sulfate. Despite these serum levels, there is initially no secondary sexual (pubic, axillary) hair development.

Adolescence ● Beginning on average at about 10,5 years in females and 11,5 years in males, there is the return of activity of the hypothalamic GnRH pulse generator, leading to increased serum levels of FSH and LH. The trigger mechanism for this resurgence is unknown, but it can be likned to attainment of a critical body mass or fat mass. , a produced by fat cells, may be connection between weight and pubertal events. In early pubert, the activity of the hypothalamic GnRH pulse generation is mostly evident overnight. Over time, this process begins to occur during the daytime (always greater at night). ● There is central sensitivity to the negative feedback effects of the sex steroids, leading to significant elevation of when sex steroids production is impaired. The functional of the hypothalamic GnRH pulse generator can be accelerated in the setting of obesity, and LH and FSH secretion can revert to the prepubertal pattern in the setting of significant weight loss, as occurs in females with anorexia nervosa. ● Usually within 6 months of the oneset of this heightened GnRH pulse generator activity in females, there is also increasing production of adrenal glands, the major source of androgens in females. In males, the testes are the main source of androgens, althougth male adrenarche also begins about 6 months after gonadarche. Sex steroid effects ● In response to FSH, both testes and enlarge, starting gonadarche. Ovarian granulosa cells produce 17B- estradiol, which cause estrogen effects that generally occur in a fixed order. ● Growth increase is one of the early effects of estrogen. Growth is stimulated by estrogen-stimulated increased production of growth hormone and insulin-like growth factor 1. Estrogens along with growth hormone and thyroid increase bone mineralization and growth

● ESTROGEN EFFECTS: -vaginal and urethral cornification -breast development, often asymmetric -linear growth -fat development -uterine development -menarche: 2-2,5 years after breast buds ● In response to LH, testicular Leydig cells produce testosterone, which is converted to dihydrotestosterone, leading to androgen effects that generally occur in the same order.

● ANDROGEN EFFECTS -psychologic changes -skin and hair oils, sweat odors -areolar growth and pigment -sexual skin pigment and folding -phallic growth -voice change -sexual hair growth -hairline recession -statural groth -muscle mass/strength ● Benign adolescent occurs in as many as 40- 60% of normal males; enough estogen relative to the amount of testosterone is produced so that breast development occurs. Gynecomastia usually starts in early to middle puberty (peak age, 13 years), before adult male concentrations of testosterone are achieve. It typically strats on one side and resolves within 2 years. Gynecomastia is more common in obese males, although true breast tissue in this setting is often difficult to distinguish from fat tissue ( lipomastia). Chronology of puberty

GIRLS ● In 85% of females, the first clinically detectable sign of puberty is breast development (), althought ovarian enlargement occure first. ● Pubic hair usually begins to develop within the next 6 months; in approximentaly 15% of females, pubic hair precedes breast development- no clinical significance. ● The female adolescent growth spurt commences near the onset of thelarche (11-13 years old) ● Axillary hair generally begins, on average, between 12 and 13 years. ● Menarche, a rather late event in female puberty, occures on average between 12,2-12,8 years, tipically 2-2,5 yeras following thelarche. It is often preceded by a whitish, non- foul smelling vaginal discharge for up to 6 months. Menstrual cycles for the 1st years after menarche are often anovulatory and irregular in frequency. Chronology of puberty Boys ● Male begin puberty at an average age of 11,5 years (9-14). The first clinically detectable sign of puberty is testicular enlargement. ● The onset of male puberty is considered to have begun when at least 1 of the 2 reaches 4 ml in volume. It takes approximately 5-6 years for the testicles to reach the average adult volume of 18 ml. ● Within 6 months after the start of testicular enlargement, pubic hair can be found; pubic hair precedes testicular enlargement in approximately 15%. ● Pubic hair is followed by the development of axillary hair at approximately 14 years of age. ● During this time, penile enlargement also occurs, reaching a mean adult length at 20 years of age. ● The male adolescent growth spurt typically occurs between the ages of 13 and 15 years, commencing when the testicular volumes reach 12 ml. ● The ability of adolescent boys to produce begins 13,5-15 years.

PRECOCIOUS PUBERTY

● It is any feature of puberty before 8 years of age in white female ( before 7 years of age in African-American females), and before 9 years of age in males (regardless of race).The family pattern must also be considered; an early onset of puberty is frequently familial. NORMAL VARIANTS

IDIOPATIC ISOLATED PREMATURE THELARCHE

● The development of the breast tissue in females before 8 years of age, with no other manifestation of puberty. Commonly begins between 2 and 3 years of age, it may be present from birth. The early breast tissue frequently regresses without intervention, but it may persist- do not usually exceed Tanner stage 3. The is not frequently advanced, and there is no associated growth spurt. ● The etiology of premature thelarche is unclear. Elevated serum estrogen levels for age have been difficult to demonstrate, althought higher levels than in age-matched normal females have been measured by the ultrasensitive estradiol assay. ● Physiologic breast enlargement also occur in neonates from placental transfer of estrogens. Most marked in the 1st week of life, it usually regresses by 1-2 months.

NORMAL VARIANTS

IDIOPATIC ISOLATED PRECOCIOUS ADRENARCHE

● Development of pubic hair, axillary hair and odor, and/or small amount of acne before the age of 8 in females and in males before the age of 9. ● It appears to result from early production of adrenal androgens. ● More commonly- in females, in obese females, in brain- injured children. ● There is no associated evidence of ( no growth spurt, no significant advencement of bone age, no increase in muscle bulk, no voice deeping, and no temporal hair recesion). In females, there is no associated clitoromegaly and no evidence of estrogen-mediated components of puberty; in males, there is no phallic or testicular enlargement. ● If a child present at a very young age, it is generally presumed that an organic cause (e.g. congenital adrenal hyperplasia) will be found. In infant males with isolated scrotal hair, typically no causes is found, and the hair subsequently falls out. ● Serum levels of DHEA/ DHEAS are consistent with reference range of Tanner staging of the hair growth and at 8 am 17-hydroxyprogesterone level is normal. ISOSEXUAL CENTRAL

● It results from activation of the hypothalamic - pituatary- gonadal axis at an earier- than- normal age. Refers to pubertal changes appropriate for the sex of the child- breast budding in females and testicular enlargement in males (conrtasexual development- pubertal features in females are mediated by male hormones-clitoromegaly, and those in males are mediated by females hormone (breast development). ● The majority of cases in females- idiopathic, whereas only a small percentage of affected males have no definable causes. ● In true male central puberty, testes enlarge (> 4ml in volume, 2 cm in lenght) and androgen production increases. If basal pituiatary gonadotropins are increasing, or if LH levels increase markedly after GnRH stimulation, the diagnosis is central precocious puberty. ● Hypothalamic hamartomas, which may be associated with ectopic secretion of GnRH or transforming growth factor-a, are common casuses of precocious puberty. Approximately 3% of children with neurofibromatosis type 1 develop central precocity, usually cased by a hypothalamic optic glioma. ● CPP in the setting of untreated or undertreated peripheral causes of puberty, such as verilizing congenital adrenal hyperplasia, is caused by premature activation of the GnRH pulse generation, presumably as a result of continuous central nervous system exposure to high levels of androgens ( or aromatized to estrogens). ● Precocious puberty with thelarche and menarche in the setting of long-standing severe untreated primary hypothyroidism can occure- the mechanism is not clear. INCOMPLETE ISOSEXUAL PRECOCITY (PRECOCIOUS PSEUDOPUBERTY)

● PP refers to gonadal or adrenal sex-steroid secretion not resulting from activation of the hypothalamic- pituitary- gonadal axis (pituitary- independent). It is caused by excessive production of or exposure to either androgens or estrogens.

A) androgen exposure or overproduction

● FEMALES ● OVARIAN TUMORS producing androgens (thecoma) and sometimes also estrogen. Gonadoblastomas, which are not always virilizing, typically occure in phenotypic females who have a Y chromosome. ● ADRENAL TUMORS-androgens are not suppressed by dexamethasone. Excessive adrenal androgens may also be porduced as a resalt of late-onset (acceleration growth rate and advanced bone age) or nonclassic congenital adrenal hyperplasia (CAH)-the androgen production can be supressed by dexamethasone.

● MALES ● If both testes are slightly increased in volume and testosterone levels are increased but LH and FSH levels are low: 1. the testes are being stimulated by human chorionic gonadotropin (hCG), which acts like LH and does not increase testicular volume, as with FSH Hepatoma, hepatoblastoma, teratoma, chorioepithelioma may producing hCG. 2. the testes are functioning autonomously- producing testosterone without gonadotropine stimulation= may be testotoxicosis (4 years of age with sign of puberty). ● Testosterone production and Leydig cell hyperplasia occur in the setting of prepubertal serum LH levels, because of a gain-of- function mutation in the gene of the LH receptor- constitutive activation. Affected males are fertile. ● If one testis is enlarged, a Leydig cell adenoma in this is probably producing excess testosterone, the tumor must be removed. The high levels of testosterone suppress LH and FSH secretion, so tha other testicle remains small. ● If androgen signs are development steadily but neither testis has enlarged, the androgen is presumed to be either from the adrenal glands ( tumor or abnormalities in the steroid synthesis enzymatic activity) or from an exogenous source. B) Estrogen Overproduction

● Estradiol is produced by the granulosa cell lining the follicles and causes vaginal discharge and breast development. The most common cause of premature progressive breast development is simple premature thelarche. In ovaries there are many small estrogen-producing follicular cysts. LH and FSH levels are low and estradiol might be elevated but minimally. ● Granulosa cell tumors are usually isolated occurrences but may occur as part if Puetze- Jeghers syndrome ( oral melanosis and intestinal polyps). ● Aromatase is the enzyme that is responsible for conversion af androgen to estrogen; aromatase excess is an autosomal dominant disorder that cal lead to increased estradiol levels. ● McCune- Albright syndrome. This disorder consist of the clinical triad of polyostotic fibrous dysplasia, hyperpigmented macules (cafe au lait spots) with irregular borders and multiple autonomous endocrinopathies (gonadotropin- independant precocious puberty, hyperthyroidism, acromegaly, hypercortisolemia). More commonly in females. Pantients have a mutation in their Gs-a gene, that occurs early in embrogenesis and results in constitutive activation of adenylyl cyclase only in affected tissue. This activation leads to the autonomous function of involved tissues. Precocity in females, often heralded by menstrual bleeding, frequently occurs before 2 years of age. The ovaries are enlarged and have many follicular cysts; the patient has elevated levels of estradiol. Later, when the GnRH pulse generation is activatied sebsequent to unabated sex steroid exposure, the patient may transition from gonadotropin- independent to central precocious puberty.

C) Vaginal Bleeding

● The usual progression of puberty in females distates that breast and uterine development begin about 2 years before the menses. ● In any case, vaginal bleeding is always a much later sign than breast development, and whenever vaginal bleeding occurs too early- especially if it ever occure before breast development starts- it must be investigated thoroughly. ● D) Gynecomastia

● Breast tissue frequently develops in male during midpubert, when the production of estrogen from testosterone in the testes temporarily overbalances the testosterone effects. Only rarely does breast tissue develop in prepubertal males, in as much as yuong males do not respond to transient gonadotropin stimulation with estrogen production. Differential diagnosis includes estrogen- producing tumors( gonadal or adrenal), exogenous estrogen, hCG- producing tumors, aromatase excess, certain types of male pseudohermaphroditism, and Klinefelter syndrome. Certain medication and illicit drugs are associated with gynecomastia. A prolactinoma should be considered, especially in the setting of . ● Evaluation of gynecomastia in prepubertal males may include karyotyping and measurment of gonadotropins, estradiol, testosterone, hCG, and prolactin level. Imaging is dictated by the results. Diagnostic Approach to Precocious Puberty

Initial evaluation should include: ● Medical history- groth patterns; excessive responses to illness (adrenal crisis);exposure to exogenous sex steroids; history of intracranial insults (hydrocephalus, meningitis) ● Review of symptoms: groth records, head size since birth, vision changes; cheadache, age at onset of androgen signs, estrogen sings; cafe-au-lait spots ● Family history: timing of maternal and paternal growth and pubertal development; sibling and cousins with early development; neurofibromatosis ● Phisical examination: vital signs, height, weight, head circumference, tooth age, cafe-au-lait spots, neurofibromata, pubic and axillary hair, bodu odor, skin and hair oils, visual fileds, optic discs, breast development, vaginal cornification/discharge, penis/ clitoris size, scrotal/lablial development, testicular volume, pubic hair stages, facial asymmetry or bone abnormalities (fibrous dyspasia of McCune Albright syndrome), neurologic status, affect of mood, intelectual ability. ● The 1st test is usually determination of bone age; - if the bone age is not significantyly advanced (within 20% of the chronologic age in the months) and not associated with an increase in hight velocity, the result suggest a normal variant, a slowly progressive process, or a process of the relative short duration. - if the bone age is significantly advanced, a workup is mandatory. ● Girls with breast development, with or without androgen effects. - random serum FSH and LH measurement; estradiol measurment - GnRH stimulation test - pelvic USG - prepubertal ovaries: USG to image adrenal glands and question about exogenous sources. - one enlarged : either functioning or solid granulosa- cell tumor - bilaterally enlarged ovaries for age: GnRH test dinstinguish between central precocity or McCune- Albright syndrome. ● Head MRI with contrast medium. ● GnRH stimulation test

With central precocity, as with normal pubert, endogenous GnRH that „primes“ the pituitary gonadotrophs is being produced, so that after administration of the single pharmacologic dose of GnRH, there is copious relase of LH.

If the precocity has a peripheral basis, the high levels of circulating estradiol, through central negative feedback, prevent the gonadotrophs from releasing LH in response to the extragenous GnRH bouls ● Girls with contrasexual androgen effects= virilization and advanced bone age - serum total testorenoe - 17-hydroxyprogesterone (CAH) - ACTH stimulation test - midnight salivary cortisol or 24-hours urine free cortisol and creatinine (Cushing syndrome- linear growth) - abdominal/ peliv MRI ● Boys with isosexual precocity - Prepubertal tests: USG of the adrenal glands, question about exogenous sources - One enlarged testis: USG of this testis for the androgen- producing tumor - Bilaterally enlarged testes for age: GnRH test to distinguish between central precocity and other causes: family testotoxicosis, hCG-producing tumor, CAH with adrenal rests or hypothyroidism. If central precocity is confirmed biochemically, head MRI with contrast. ● Tests to consider, in either sex, depending on clinical presentation - serum hCG - prolactin - T4 or TSH Treatment of precocious puberty

● Not all cases of precociuos puberty necessitat treatment ● Cases of idiopathic precociuos thelarche and andrenarche should be monitored. ● In addition, not all children with central precocious puberty require treatment, inasmuch as a significant number of cases are either slowly progressive and/or transient. ● Unless there is rapid progression and/or significant psychosocial dissiculties, most children with central precocity should be observes for a 3- to 6 months period before pubertal reversal therapy is initiated. ● The reason that favor treatment include preservation of acceptable final height, prevention of psychologic trauma ( at an early age), reversal of mature physical appearance. ● If the decision is made to reverse puberty, the goal of therapy is to inhibit secretion and/or effects of estrogens in females and androgens in males 1. Central precocious puberty

● The goal of the therapy is to inhibit secretion of gonadotropins and reduce productrion of sex steroids by the administration of the GnRH analogs with the prolonged duration of action. This causes down- regulation of pituitary GnRH receptors, preventing the response to endogenous GnRH and thus decreasing LH and FSH secretion. Several doses of GnRH are necessary to produce the antagonistic response because the treatment initialy stimulates the axis and only later results in down regulation of pituitary GnRH receptors. ● Therapy is stopped at about 11 years in female and 12 years in malesso that puberty can resume. Successful GnRH agonist treatment is associated with stabilization of the androgen effects in males and estrogen effects in females. ● Hight velocity and the rate of bone age maturation should slow. ● Once GnRH analog therapy is discontinued, reactivation of the hypothalamic- pituitary- gonadal axis occurs within 12 months

● Large tumors in the hypothalamic- pituitary region are surgically removed, and both the tumor or the surgery can precipitate central precocious puberty. However, hypothalamic hamartomas are benign and tend to grow very slowly, therefore, the surgery is usually not recommended. Precocious Pseudopuberty (Incomplete Isosexual Precocity).

● Treatment is directed at the underlying cause. ● The precocious puberty of McCune-Albright syndrome is treated with inhibitors (testolactone or anastrazole) of aromatase, the enzyme that convers androgen to estrogen. The result of this approach are variable, and sometimes a GnRH agonist must be added if central puberty is also present. ● Ketoconalzole is an effective therapy for familial testotoxicosis (due to a constitutively active LH receptor), because it has the desirable and reversible side effect of interfering with sex steroid synthesis; ● Spironolactone is an blocker. THANK YOU