PRECOCIUS PUBERTY 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 adrenarche 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 breast development, which usually begins between 8 and 12 years old. Among white girls, the mean age of oneset of breast development and pubic hair growth occurs at approximately 10 years old, with menarche 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 estrogens 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 estrogen 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-estradiol 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 testosterone for 6-12 months, leading to further genital development. Childchood ● By 2 years of age, serum gonadotropin 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. Leptin, a hormone 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 gonadotropins 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 ovaries 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 hormones 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 gynecomastia 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 (thelarche), 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 testicles 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 sperm 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 bone age 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 virilization ( 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