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57 Cards in this Set

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2 types of abnormal puberty:
Precocious puberty

Delayed puberty
Puberty : Definitions--
*The process of physical changes by which a child's body matures into an adult body capable of sexual reproduction to enable fertilization.

*The period of becoming first capable of reproducing sexually marked by maturing of the genital organs, development of 2˚ sex characteristics, and in the human by the first occurrence of menstruation in the female.
Thelarche:
Gynecomastia:
Menarche:
Amenorrhea:
Spermarche:
Pubarche:
Adrenarche:
Gonadarche:
Thelarche: breast development in females
Gynecomastia: breast development in males
Menarche: first onset of menses
Amenorrhea: absence of menses
Spermarche: first appearance of sperm
Pubarche: pubic hair development

Adrenarche: secretion of adrenal androgens by adrenal cortex; Dehydroepiandrosterone (DHEA) and it’s sulfate DHEAS – weak androgens

Gonadarche: secretion of gonadal sex steroids (testosterone and estrogen)
HPG axis role in puberty:
GnRH--> gonadotrope --> LH/FSH --> gonads
GnRH--> gonadotrope --> LH/FSH --> gonads
Gonadotropin action on the gonads:
androstendione gets converted to Estradiol
Action of testosterone:
Action of testosterone:
*Prenatal differentiation of wolfian ducts and external genitalia (IF 5α reductase is present)
*Development of male secondary characteristics (male hair distribution, penile growth, laryngeal enlargement, ↑ muscle mass)
*Causes pubertal growth spurt
*Maintains spermatogenesis in sertoli cells (paracrine effect)
↑ size and secretory activity of epidymis, vas deferens, prostate and seminal vesicles
↑ libido
Action of estrogen:
*Maturation and maintenance of fallopian tubes, uterus, cervix and vagina
*Development of female secondary sexual characteristics
*Breast development
*Maintains pregnancy
Pubertal timing (ages):
outside of 2 SDs is abnormal--precocious or delayed
outside of 2 SDs is abnormal--precocious or delayed
Normal Puberty: mean ages
*Breast development/thelarche: 10.5 yrs

*First menses/menarche: 12.9 yrs White girls; 12.2 yrs African American

*Testicular enlargement: 11.5 yrs

*Peak growth velocity: 12 yrs girls boys 13.5 to 14 yrs
Tanner Stages: Girls:
1: Pre-pubertal
2: Breast bud
3: Further enlargement
4: Areola and papilla  -  secondary mound
5: Adult
1: Pre-pubertal
2: Breast bud
3: Further enlargement
4: Areola and papilla- secondary mound
5: Adult
Tanner staging: Pubic hair:
1: Pre-pubertal
2: Sparse hair along labia
3: Darker,coarser, curlier over junction of pubis bone
4: Adult type : no spread to medial thighs
5: Spread to medial thighs
Prader Orchidometer :  to assess testicular  volume 
 (testicular enlargement is first sign of puberty in boys).
Prader Orchidometer : to assess testicular volume
(testicular enlargement is first sign of puberty in boys).
Tanner Stage: Boys (testis and penis):
1: Pre-pubertal (<3 cc testis;<2.5 cms)
2: Testicular enlargement (~4 cc; >2.5 cms)
3: increased length
4: increased breadth and glans
5: adult
LH secretions related to Tanner stages:
Stage 2: LH at night only
Stage 3/4: day and night LH

*LH heralds onset of puberty--> needed to get DHT
Precocious puberty:
*Central/Gonadotropin-dependent:
activation of the hypothalamic-pituitary gonadal axis (↑ LH, FSH, testosterone or estradiol)

*Peripheral/Gonadotropin-independent:
elevated sex steroids from ovary or testes
(↑ testosterone or estradiol, ↓ LH, FSH)
Etiology of Central Precocious Puberty:
*Hypothalamic tumors
-Hamartomas (most common organic cause)
gliomas, astrocytomas, ependymomas

*Pituitary tumors: Craniopharyngiomas

*CNS anomalies
-Static encephalopathy (hypoxia, trauma, infection)
-Hydrocephalus
-Low dose irradiation

*Idiopathic: More common in girls (most common in all kids)
Etiology of Peripheral Precocious Puberty:
-discuss environmental causes, ovarian disorders, and testicular disorders:
*Environment
-lavender oil, tea tree oil
-E/T creams, gels

*Ovarian disorders
-Granulosa cell tumors
-Follicular cysts
-McCune-Albright Syndrome
-Severe Hypothyroidism**

*Testicular disorders
-Familial male-limited precocious puberty
-Leydig cell tumor
-McCune-Albright Syndrome
-gonadoblastoma

*Don't memorize all of these*
Etiology of Peripheral Precocious Puberty:
-discuss hCG secreting tumors and Adrenal disorders:
*hCG-secreting tumors
-Dysgerminoma
-Teratoma
-Chorioepithelioma
-Choriocarcinoma
-Hepatoblastoma

*Adrenal disorders
-Adrenal adenoma
-Adrenal carcinoma
-CAH
-Premature Adrenarche

*Don't memorize all of these*
Severe hypothyroidism effect on puberty:
-High TSH --> binding to FSH receptor (remember they have a common alpha subunit) in ovary --> increased estradiol secretion --> breast development

-TSH can also bind to receptors in testicles to stimulate inhibin and spermatogenesis
Central Precocious Puberty:
*Thelarche < 8 y.o. in girls
*Testicular enlargement < 9 years in boys.
*1/5000 to 1/10,000 children
*10-23x more common in girls than boys
*Etiology:
Girls: Idiopathic (70-90%)
Boys: CNS lesions (60-94%)
Schematic of early puberty in females:
Schematic of early puberty in males:
Male with central precocious puberty with sixth nerve palsy secondary to intracranial astrocytoma
*Male with central precocious puberty with sixth nerve palsy secondary to intracranial astrocytoma
*Right eye is esotropic
*The kid is muscular
*Thin scrotum
*Thelarche and vaginal bleeding at 2 ½ yrs
A. At 3½ years , BA 7 yrs
B. At age 5 8/12 yrs
C. At age 8 years – BA 14 yrs
*Final adult height: 142 cms ( 56” or 4’8”)
Dx of CPP:
*GnRH level? a very short half-life of 2-5 mins and is confined in the hypothalamic-portal circulation.
*Old test: GnRH stimulation testing: gold standard (LH predominant response)

*Current test: Serum LH by ICMA test >0.3 IU/L is consistent with central puberty
McCune Albright Syndrome:
*peripheral precocious puberty, café-au-lait spots and firbous dysplasia of bones
*peripheral precocious puberty, café-au-lait spots and firbous dysplasia of bones
McCune Albright Syndrome
*McCune Albright Syndrome
*increased sex steroids
*low LH/FSH
Pathophysiology of MAS:
*Mutation in the Gsα gene that occurs early in embryogenesis ( somatic or post-zygotic)

*Results in constitutive activation of adenylyl cyclase in multiple affected tissues

*Unregulated hormone production independent of the normal stimulatory factors from the hypothalamus or pituitary gland.
*Large penis noted at 6 wks
*Pubic hair at 6-9 months
*At 18 months 
*Tanner 4 penis, 3 pubic hair, and testicular volume 3cc
husky voice
muscular
*Low LH/FSH, High testosterone
*Large penis noted at 6 wks
*Pubic hair at 6-9 months
*At 18 months
*Tanner 4 penis, 3 pubic hair, and testicular volume 3cc
husky voice
muscular
*Low LH/FSH, High testosterone
Familial Male-Limited Precocious Puberty AKA Testotoxicosis
Familial Male-Limited Precocious Puberty AKA Testotoxicosis:
*Presentation
-Typically at ≤ 4 years old
-Signs of puberty, rapid virilization and growth acceleration

*History
-Frequently a positive family history of FMPP

*Low LH/FSH, High testosterone
*Penis is more advanced than testicles
*Male-only counterpart of McCune-Albright (McA happens in both sexes)...LH receptor is mutated.
Pathogenesis of testitoxicosis:
*Normal Production
LH-->Leydig cell receptor--> adenyl cyclase stimulated  testosterone

*Mutations
Constitutively active Leydig cell receptor--> adenyl cyclase stimulated--> testosterone
Leydig Cell Hyperplasia in testitoxicosis
Treatment for Precocious puberty:
*Central Precocious Puberty: GnRH agonist

*Tumors (testicular/ovarian): surgery, chemotheraphy

*McCune Albright Syndrome: Tamoxifen (estrogen antagonist)

*Familial male limited precocious puberty/Testotoxicosis: anti-androgen or aromatase inhibitors
Why do we use GnRH agonists to treat central precocious puberty?
*1978 study--Belchetz cut out the hypothalamus of monkeys and gave a steady concentration of GnRH --> low LH/FSH

*When he have GnRH in a pulsatile manner --> high LH/FSH

*Therefore, we give a continuous GnRH agonist to kids with CPP, which keeps LH/FSH low in them.
Treatment for CPP?
*GnRH agonist
*Treatment of choice since 1981
*Continuous administration suppresses FSH and LH levels and inhibits gonadal activity (by a desensitization mechanism).
Example of GnRH agonists we use?
-In the U.S., Leuprorelin (Lupron) and Histrelin
Dosages and costs of GnRH agonist treatment?
histrelin is a continuous subdermal med--no shots; implant lasts about a year. Maybe longer.
Delayed puberty definition:
*Absence of thelarche (breast bud) at 13 yrs of age in girls

*Absence of testicular enlargement at 14 yrs of age in boys
Classification of delayed puberty:
*Constitutional delay in growth and puberty (CDGP)
*Hypogonadotropic hypogonadism
*Hypergonadotropic hypogonadism
*Genetic defects of the Hypothalamic-pituitary axis
Differential diagnosis of delayed puberty:
hypergonadotropic--no negative feedback AKA 1˚ gonadal failure

hypogonadotropic AKA 2˚ gonadal failure
Schematic of the hypothalamic-pituitary-gonadal axis in a normal patient and in the setting of primary and secondary hypogonadism:
CDGP:
*Delay in onset of puberty
*Usually shorter than peers
*NORMAL growth velocity
*Positive family history of pubertal delay in a parent

*Adrenarche (pubic hair) is characteristically delayed along with gonadarche (breast bud/testicular enlargement)

*TREATMENT: Reassurance or short course of testosterone enanthate or cypionate--> 2˚ sex traits.
Define Hypogonadotropic hypogonadism:
Absent or decreased ability of the hypothalamus to secrete GnRH or the pituitary gland to secrete LH and FSH
Causes of Hypogonadotropic hypogonadism:
*CNS disorders:
-Tumors (CRANIOPHARYNGIOMA ): most common
-Acquired CNS d/o: TB, sarcoid, trauma
-Congenital disorders: Septo-optic dysplasia (absent septum pellucidum)
-Irradiation: e.g. ( CNS leukemia requiring 18-Gy dose radiation

*Genetic defects of the hypothalamic-pituitary axis
A. Isolated gonadotropin deficiency: Kallmann’s syndrome
B. Multiple pituitary hormone deficiency
C. Miscellaneous: Prader-Willi syndrome, chronic disease, anorexia nervosa, hypothyroidism
Why can hypothyroidism cause hypogonadotropic hypogonadism?

How can it also lead to precocious puberty?
*TRH and TSH levels will rise; thus raising PRL levels, which suppress LH/FSH.

*High TSH can cross react and stimulate the LH/FSH receptors in the ovary/testicle (alpha subunit)
3 labs to get when someone presents with delayed penile growth (case was a 20 year old with 3.5cm penis and 2cc testes)
LH
FSH
Testosterone
*Turns out case guy had a FGFR1 mutation
Genes involved in pubertal development:
Don't need to memorize; just be aware of the mutations out there.
Hypergonadotropic hypogonadism:
implies that hypothalamic pituitary component of pubertal signalling has been activated through lack of negative feedback that is normally exerted by actions of sex steroids.

*Males
A. Klinefelter’s syndrome
B. Other forms of primary testicular failure
(chemotherapy and radiation to testicles)
C. Anorchia (no testes) or cryptorchidism (undescended)

*Females
A. Turner’s syndrome
B. Other forms of primary ovarian failure (chemotherapy, radiation to ovaries, autoimmune oophoritis)
*Seminiferous tubular dysgenesis AKA Klinefelter!!!!!!
*Some have Leydig cell problems, need testosterone replacement
Klinefelter’s syndrome:
*Most common form of primary testicular failure
*Incidence: 1:800- 1,000
*Physical exam: decreased upper:lower segment ratio, small, firm testes, developmental delay, learning disability
*Leydig cell function is less affected than seminiferous tubule function
*Aka syndrome of seminiferous tubule dysgenesis
Treatment for Klinefelter:
Treatment : Testosterone preparations: depot IM injections vs. gel (look out for that gel!)
Turner’s syndrome:
*Syndrome of gonadal dysgenesis
*45 X or mosaicism (45X, 46XX, 45X, 47XXX, etc)
*“streak gonads” – fibrous tissue without germ cells

*Features: short stature (most common), bicuspid aortic valve ( most common cardiac defect)

*No estrogen, high FSH
Turner syndrome
Physical stigmata of Turner syndrome (diagram):
turner
turner
Treatment for Turner syndrome:
Growth hormone for short stature
Estrogen for pubertal induction