Puberty

CHAPTER 23. PUBERTY


Jan. 27, 1997 1st year resident J. W. Lee. M.D.




NORMAL PUBERTAL DEVELOPMENT


  • Definition: as period during which secondary sexual characteristics begin to develop & the capability of sexual reproduction is attained.

    Hormonally - Resetting of the classic (-) gonadal steroid feedback loop

    -> alterations in circadian & ultradian (frequent) gonadotropin rhythms

    -> acquisition of (+) estrogen feedback loop

I. Factors affecting time of onset



    Genetic; no doubt (major determinants), Nutritional state, General health, Geographic location,
    Exposure to light, Psychologic state.


II. Physical changes during puberty



  • Occur in an orderly sequence over a definite time frame.
  • Any deviation from this sequence or time frame : abnormal



A. Tanner Stage



  • In girls, Duration of pubertal development : 4.5yrs. ---> Fig. 23.2
  • Generally, accelerated growth, breast budding (1st changes)

    --> pubic hairs, peak growth velocity, menarche. --> Fig. 23.3


    ♤ Stage 1:

    Prepubertal stage --> no palpable breast tissue,

    areolae < 2cm, nipple - inverted. flat / raised.


    ♤ Stage 2:

    Breast budding occurs, visible & palpable mound of breast tissue.

    areolae ↑, skin of the areolae -> thin. Nipple develops to varying degree.


    ♤ Stage 3:

    Further growth & elevation of the entire breast.

    Nipple - generally at / above the midplane.


    ♤ Stage 4:

    Projection of the the areola & papilla above the general breast contour in a
    secondary mound.


    ♤ Stage 5:

    Mature breast, more pigmented nipples below the midline of breast tissue.

    c.f. Full breast development ; over 3 -3.5 years

    breast size ; no Indication of breast maturity

    --> Fig 23.4


    ♤ Stage 1;

    some nonsexual hair presnet.

    ♤ Stage 2;

    1st appearance of coarse, long, crinkly pubic hair along the labia majora

    ♤ Stage 3;

    coarse, curly hair extends onto the mons pubis

    ♤ Stage 4;

    adult hair in thickness and texture , but not extend onto the inner aspects of the thighs

    ♤ Stage 5;

    extends onto the thighs

    c.f Male pubertal sexual maturation; based on genital size & pubic hair development


B. Height and Growth Rate



  • Plotting height increments (i.e. growth velocity) against the phase of puberty allows one to see
    elationships during puberty --> Fig. 23.2
  • Girls' reach peak height velocity early in puberty prior to menarche. -> limited growth potential
    following menarche. c.f. boys ; approximately 2 yrs later than girls


  • Average height increment during growth spurt ; boys (28 cm), girls (25 cm)
    c.f. Adult men ; average 10 cm taller than adult women
  • Hormonal control of pubertal growth spurt -> complex ; GH, IGF-1, gonadal steroids

    c.f. adrenal androgen - less important


  • Estimation of bone / skeletal age: X-rays documenting the development of bones in the
    nondorminant hand (mc), knee, or elbow to standards of maturation for the normal population
  • Skeletal age; a/w pubertal stage >> chronologic age
  • Adjusted midparental height



    • boys ; mother's height + 13 cm
    • girls ; father's height - 13 cm

      --> determining the mean of the Ht of the parents; including the adjusted height of the opposite sex
      parent --> the calculated predicted Ht ±8.5 cm (3- 97 percentile)



  • Changes in body composition during pubertal development.


    * Prepubertal boys & girls : LBM, skeletal mass, & body fat are equal.

    * By maturity, . Men : 1.5 times the LBM


    • Women : 1.5 times the skeletal mass.

      c.f. women --> twice as much body fat as men.



III. Hormonal Changes During Puberty



  • 10wks of gestation . GnRH (+) in the hypothalamus.


    • LH & FSH (+) in the pituitary gland.



  • Before birth, Gn levels↑ in both female & male fetuses, (but, FSH : higher in females)


  • At birth, Gn & sex steroid concentration : still high. but, during 1st several weeks of life, the level
    decline --> remain low during the prepubertal years.



  • Hypothalamic - pituitary unit : suppressed by the extremely low levels of gonadal steroids present in
    childhood. (--> Gonadal suppression of Gn secretion, demonstrated by higher Gn levels in children
    with gonadal dysgenesis and these who undergo gonadectomy before puberty.)


  • Several hormonal changes a/w pubertal development.



    • Early in puberty, ↑ sensitivity of LH to GnRH.
    • Sleep-entrained ↑in both LH & FSH

      * Nocturnal ↑ in Gn level
    • In boys, circulating testosterone level ↑

    • In girls, ↑ E2 the next day

      (d/t additional synthetic steps required in the aromatization of estrogens from androgens)


  • Basal levels of both FSH & LH : ↑

    * LH levels : eventually becoming greater than FSH.

    --> Fig 23.6


  • ↑Adrenal androgen secretion : important in stimulating adrenache, the appearance of pubic &
    axillary hair, in both boys & girls.

    c.f. Major adrenal androgen : DHEA & its sulfate (DHEAS)


  • E1/E2 ratio : ↓through puberty, --> ovarian production of E2 becomes increasingly important
    & peripheral conversion of androgen to E1 become less important during maturation.



    IV. Mechanisms underlying Puberty



    • Poorly understood: " CNS program " must be responsible for initiating puberty.
    • Hypothalamic - pituitary - gonadal axis develops in two distinct stages during puberty.




      • Sensitivity to the negative / inhibitory effects of the low levels of circulating sex steroids present in
        childhood. --> decrease early in puberty.
      • Late in puberty, there is maturation of the positive / stimulatory feedback response to estrogen,
        which is responsible for the ovulatory midcycle surge of LH.



    • Current Evidence: CNS inhibits the onset of puberty until the appropriate time.



      • Neuroendocrine control of puberty : mediated by GnRH-secreting neurons in the medial basal
        hypothalamus (--> act together as an endogenous pulse generator)
      • GnRH pulse generator is reactivated (disinhibited) --> amplitude & frequency of GnRH pulses
        -->↑Gn -->↑ Gonadal steroid secretion.

        but, what causes this " disinhibition " of GnRH release : unknown.




    ABERRATIONS OF PUBERTAL DEVELOPMENT.




    CLASSIFICATION --> TABLE 23.1




    1. Delayed / interrupted puberty :



      • fail to develop any 2' sex characteristics by age 13,
      • not had menarche by age 16.
      • 5 or more yrs have passed since the onset of pubertal development without attainment of menarche.



    2. Asynchronous pubertal development : deviate from the normal pattern
    3. Precocious puberty : pubertal development beginning before the age of 8years.


      • True (central origin) : activation of HPO axis.
      • Pseudo (pph origin) : secretion of hormones in the periphery (commonly by tumor)



    4. Heterosexual puberty :development that is characteristic of the opposite sex occurring at the expected
      age of normal puberty.



    I. DELAYED / INTERRUPTED PUBERTY. --> FIG. 23.8.



    A. Anatomic Abnormalities of the Genital Outflow Tract.




    • Mullerian agenesis & dysgenesis : mature 2' sex characteristics and any of a No of disorders of the
      outflow tract & uterus.
    • Table 23.9
    • Incidence : 0.02%
    • MRKH syndrome : occur as a part of a syndrome of malformation that include abnormalities of the
      skeletal & renal system.
    • Imperforate hymen : hydrocolpos / hydrometrocolpos.
    • Obstruction / malformation of the distal genital tract: must be distinguish from androgen insensitivity.


    B. Hypergonadotropic & Hypogonadotropic Hypogonadism. --> Fig 23.8




    • Karyotype : determined in any individual with delayed puberty & ↑basal FSH conc.
    • Forms of Gonadal Failure



      1. Turner's Syndrome



        • 45X, mosaicism (45X/46XX ; 45X/46XY)


        • generally grow slowly,


        • associated stigmata : lymphedema at birth, webbed neck, multiple pigmented nevi, disorders of
          heart, kidney (most commonly horseshoe), & great vessel (most commonly COA). DM,
          thyroid ,Dz, essential HT, other autoimmune disorders.


        • Not develop breasts at puberty, some pubic / axillary hair may be develop because appropriate
          adrenarche can occur with failure of thelarche.


        • less severe short stature & some adolescent development

          --> occur with chromosomal mosaicism. (Treatment)



        1. GH
        2. Estrogen to promote sexual maturation, : cca 12 ~ 13 yrs of age, and after GH therapy is
          completed.


        3. Because the intent is to mimic normal pubertal development, low-dose estrogen alone
          (such as 0.3 ~ 0.625mg conjugated estrogen orally each day)


        4. Progestins (5 ~ 10mg MPA orally for 12 ~ 14 days every 1 ~ 2 months)

          : to prevent endometrial hyperplasia after the patient 1st experience vag. bleeding or after
          6months of unopposed estrogen use if the patient has not yet had any bleeding.


        5. The dose of estrogen is increased slowly over 1 ~ 2years until the patient is taking about twice
          as much estrogen as is administered to postmenopausal women.


        6. Counseled regarding the emotional & physical changes that will occur with therapy.



      2. Mosaic Forms of Gonadal Dysgenesis



        • Decision to initiate therapy with exogenous estrogen : based mainly on circulating FSH levels
          (because FSH levels in the normal range for the pts age imply the presence of functional gonads)




      3. Pure Gonadal Dysgenesis


        : 46XX/46XY phenotypic females who have streak gonads



        • occur sporadically or may be inherited as an AR trait or as an X-linked trait in XY
        • FSH level ↑ : because the streak gonads produce neither steroid hormones nor inhibin.
        • Swyer's syndrome : gonadal dysgenesis in 46XY
        • Surgical extirpation is warranted in 46XY Karyotype to prevent development of germ cell
          neoplasm.




    C. Hypogonadotropic Hypogonadism.



    ? Hypothalamic-pituitary disturbance : usually a/w low levels of circulating Gn (both LH & FSH <
    10mIU/ml)

    --> DDx. constitutional delay : most common cause.


    1. Isolated Gn Deficiency.


    ? : as part of a number of syndrome in which there is a disorder of the GnRH generator rather than a failure of the pituitary gland



    1) Kallmann syndrome



    • Triad : Anosmia, Hypogonadism, Color blindness.
    • Associated defect : cleft lip & palate, cerebellar ataxia,, nerve deafness, abnormalities of thirst & vasopressin release.
    • Olfactogenital dysgenesis : embryologically, GnRH neurons originally develop in the epithelium of the olfactory placode & normally migrate into the hypothalamus.
    • Gene defect : KALIG-1 (Kallmann syndrome interval gene -1) --> at X ch.
    • Clinically, sexual infantilism, eunuchoid habitus, some degree of breast development.,
    • 1' amenorrhea,
    • Ovaries : usually small, with follicles seldom developed the primodial stage.
    • Circulating Gn levels : usually very low but almost invariably measurable.
    • respond readily to pulsatile administration of exogenous GnRH,



    2) Prader-Labhardt-Willi syndrome



    • Obesity, short stature, hypogonadism, small hands & feet (acromicria), MR, infantile hypotonia,
      Laurence-Moon-Bardet-Biedl syndrome (retinitis pigmentosa, postaxial polydactyly, obesity,
      hypogonadism)
    • Multiple pituitary hormone deficiency




    2. Tumors of the Hypothalamus & Pituitary.



    • Craniopharyngiomas : common in children, usually suprasellar location, asymptomatic well into
      the 2nd decade of life.
    • Sx.: headache, visual disturbance, short stature, growth failure, delayed puberty, D.I.
    • Lab : hypogonadotropinism,
      hyperprolactinemia (result of interruption of hypothalamic dopamine inhibition of PRL
      release.)



    3. Other Central Nervous System Disorders.



    • Infiltrative Ds : Langerhans-type histocytoosis....
    • Irradiation of CNS for Tx. of any neoplasm / leukemia.
    • Severe chronic illnesses (<-- malnutrition)


      c.f. Regardless of the cause, weight loss to less than 80 ~ 86% of ideal body wt. often will result in
      hypothalamic GnRH deficiency.



    4. Anorexia Nervosa & Bulimia.



    • Although many anoretic girls experience amenorrhea after pubertal development has begun, if the
      disorder begins sufficiently early, pubertal development may be delayed / interrupted.
    • Associated findings : relentless pursuit of thinness, amenorrhea, sometimes preceding the weight
      loss, extreme inanition, obsessive-compulsive personality often characterized by overachivement,
      distorted & bizarre attitude eating, food, or weight, distorted body image.
    • Bulimia : because normal BWt is commonly maintained, unusual delayed development /
      amenorrhea.



    5. Hyperprolactinemia.



    • Low levels of LH & FSH : a/w hyperprolactinemia.
    • Cause : pituitary prolactinoma, primary hypothyroidism, empty sella syndrome.



    II. Asynchronous Puberty.



    • Characteristic of androgen insensitivity.(i.e. testicular feminization)
    • 46XY : bilat. testes, female external genitalia, blindly ending vagina, & no mullerian
      derivatives (i.e. uterus, tube)

      c.f. Incomplete androgen insensitivity : clitoral enlargement & labioscrotal fusion at puberty


    • Always related to some abnormality of the androgen receptor / of androgen action.



      • Sertoli cells of the testis make antimullerian hormone (AMH) --> normal mullerian regression.
      • Testes : normal in size, located anywhere along the path of embryonic testicular descent, in the
        abdomen, inguinal canal, or labia.



    • Gonadal neoplasia :



      • low risk before 25yrs of age. but, increase with age.
      • Exogenous estrogen : should be provided after gonadectomy.



    • Dx.

      • Typical physical finding
      • Testosterone (normal / ↑), LH ( normal / ↑), FSH (normal)
      • confirmed by 46XY karyotype.



    • Familial genetic counselling : XR



    III. Precocious Puberty



  • Gonadotropin-dependent (central origin)

    ? ? Gonadotropin-independent (peripheral origin)



  • Evaluation



    • measurement of basal gonadotropin
    • TFT
    • LH (hCG) ↑; gonadotropin producing neoplasm (pinealoma, chorioCa, hepatoblastoma)
    • Gonadotropin ↓; isosexual development ; E2

      heterosexual development ; androgen (T, DHEAS, 17OHP)

    • E2 ; estrogen- secreting neoplasm;
    • Testosterone ; androgen-producing neoplasm of ovary or adrenal gland
    • 17 OHP ; 21-hydroxylase deficiency
    • DHEAS ; CAH
    • Brain MRI or CT
    • Bone age

      ---> Fig. 23.16




    • Precocious thelachy ; precocious breast budding only

      ; increase sensitivity of breast to low level of estrogen or to increased estradiol
      secretion by follicular cysts


    • Precocious pubarchy of adrenarchy ; appearance of pubic of axillary hair alone

      ; increased sensitivity to low levels of androgen

      --> merely frequent follow up


    • Constitutional sexual precosity; most common cause, familial, tail of Gaussian curve



    A. Central (true) precocious puberty



    1. Constitutional or idiopathic
    2. Hypothalamic lesion; tumor, congenital abnormality, trauma, infection

    B. Precocious puberty of peripheral origin



    1. Neoplasm of producing of estrogen, androgen
    2. Small functional ovarian cyst
    3. Endocrinopathies
    4. Exogenous estrogen exposure



    • McCune -Albright syndrome



      a) Polyostotic fibrous dysplasia of bone

      b) Irregular cafe au lait spots

      c) Hyperfuctioning endocrinopathies


  • Congenital Adrenal Hyperplasia

    • heterosexual precocious puberty


    1) 21-hydoxylase deficiency




    • 1/15000, Autosomal Recessive, HLA complex on the chromosome 6
    • Classification


      1. classic ; typically identified at birth because of genital ambiguity
      2. salt- wasting ; impairment of mineralocorticoid secretion
      3. Late-onset (nonclassical) ; heterosexual development occurs at the expected age of puberty




      • impairment of conversion of 17 a-hydroxyprogesterone to 11-deoxycortisol

        progesterone to deoxycorticosterone

        -->androgen ↑-->ambiguous genitalia (enlarged clitoris, fusion of labioscrotal folds, urogenital sinus)
        ※ internal organ ; normal

      • salt- wasting form ; hyponatremia, hyperkalemia, hypotension
      • during childhood ; grow rapidly but have advanced bone age

        -> early closure of epiphysis

        -> short stature

      • Dx ; genital ambiguity and increased 17a - hydroxyprogesterone


    2) 3b - hydroxysteroid dehydrogenase

    3) 11 - Hydroxylase Deficiency



    ♣ Treatment of CAH


    • hydrocortisone (10 -20 mg/m2), intent; morning 17 OHP level ; 300 -900 ng/dl
    • growth velocity and bone age should be monitored
    • mineralocorticoid ; whether of not they are salting
    • reconstructive surgery




    IV. Heterosexual Pubertal development




    • Most common cause; PCO (LH-dependent hyperandrogenism)
    • Clinical manifestation


      1. somewhat overweight
      2. delayed menarche
      3. LH, androgen ; elevated
      4. in anovulatory women , E1 >> E2
      5. heterosexual development


    A. DDx & Evaluation.




    1. Measurement of 17 -hydroxyprogesterone in all women who develop hirsuitism.



      • ↑ 100-fold with classic 21-OHase deficiency.
      • may or may not be elevated in nonclassic late-onset forms of the disorder.



    2. 17 -hydroxyprogesterone level : identify various forms of 11-OHase deficiency.
    3. PCO : ↑ basal levels of DHEAS & 17 -hydroxyprogesterone
    4. To screen for CAH, 17 -hydroxyprogesterone should be measured in early morning.
    5. In women with regular cyclic menses, it is important to measure 17 - hydroxyprogesterone only in the follicular phase, because basal levels increase at midcycle and in the luteal phase.



      * Basal Levels of 17 -hydroxyprogesterone



      > 800ng/dl : diagnostic of CAH.

      300 ~ 800ng/dl : require stimulatory testing with corticotropin to distinguish between PCO & CAH.

      < 300ng/dl : nonclassic 21-OHase deficiency -- require stimulatory testing


      * Cosyntropin Stimulation Test


      : mc used stimulatory test, measurement of 17 -hydroxyprogesterone 30min. after administration of a
      bolus of 250 g of synthetic Cortrosyn.



      • Normal : seldom exceed 400ng/dl
      • Classic 21-OHase deficiency : 3000ng/dl or higher.
      • Nonclassic 21-OHase deficiency : 1500ng/dl or more.
      • Heterozygous carrier : 1000ng/dl

        c.f. Glucocorticoids (dexamethasone)administration.


        • ↓ 17 -hydroxyprogesterone in CAH
        • not in vililizing ovarian & adrenal neoplasm




      * Hirsuitism



      • DDx (CAH : idiopathic hirsuitism)



        • idiopathic hirsuitism : regular ovulatory mens. normal 17 -hydroxyprogesterone level



    Genital Ambiguity at Birth



    • Genital ambiguity should be evaluated promptly (d/t life-threatening Cx.)
    • Initial evaluation



      • Cytogenetic & endocrine studies
      • To exclude CAH. (mc cause , serum sodium, potassium, 17 -hydroxyprogesterone, urinary excretion
        of 17-ketosteroids, pregnanetriol, tetrahydrodeoxycortisol.)
      • Antimullerian hormone measurement in infants




    1. Physical Signs


      c.f. normal male : a single midline frenulum on the ventral side of the phallus.

      normal females : 2 frenula lat. to the midline.



    • Gonad : location & consistency --> helpful in deducing its composition.

      c.f. : gonad located in the labial / inguinal regions --> almost always contain testicular tissue.


    2. Dx. & Mx.




      c.f. sex-of-rearing : changed before 2yrs of age without psychologically damaging child.



    • Surgery to make external genitalia. : (mc) clitoral resection & clitorectomy.
    • Prenatal check of 21-OHase deficiency :


      • AF (↑ 17 -hydroxyprogesterone / ↑21-deoxycortisol)
      • CVS, amniocentesis.

        c.f. prenatal Tx. : dexamethasone. (maternal Cx. ↑)

    3. Teratogen. --> Table 23.3