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
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.
Asynchronous pubertal development : deviate from the normal pattern
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)
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.
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
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)
GH
Estrogen to promote sexual maturation, : cca 12 ~ 13 yrs of age, and after GH therapy is
completed.
Because the intent is to mimic normal pubertal development, low-dose estrogen alone
(such as 0.3 ~ 0.625mg conjugated estrogen orally each day)
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.
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.
Counseled regarding the emotional & physical changes that will occur with therapy.
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)
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
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.
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)
mineralocorticoid ; whether of not they are salting
reconstructive surgery
IV. Heterosexual Pubertal development
Most common cause; PCO (LH-dependent hyperandrogenism)
Clinical manifestation
somewhat overweight
delayed menarche
LH, androgen ; elevated
in anovulatory women , E1 >> E2
heterosexual development
A. DDx & Evaluation.
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.
17 -hydroxyprogesterone level : identify various forms of 11-OHase deficiency.
PCO : ↑ basal levels of DHEAS & 17 -hydroxyprogesterone
To screen for CAH, 17 -hydroxyprogesterone should be measured in early morning.
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.