Puberty Flashcards
Normal puberty order
Growth acceleration (not maximal) -> Thelarche -> Adrenarche/Pubarche -> Peak height velocity -> Menarche
Etiology of thelarche
initial activity of HPO axis -> estrogen
Etiology of adrenarche/pubarche
Adrenal hormones -> hair growth
Zona reticularis: High P450c17, Low 3BHSD
How long between adrenarche and pubarche
2-3 years
How long between peak height velocity and menarche
6 months
What mediates peak height velocity?
GH -> IGF-1 -> IGFBP-1/3
First hormonal change in puberty
Nighttime LH pulses
- One year before breast buds form, nocturnal LH pulses change
- LH levels exceed those of FSH
- LH amplitude increases x10, FSH amplitude increases x 2 -> decrease in the FSH/LH ratio
- LH amplitude then rises to 20-40x greater than pre-pubertal levels
- LH bioactivity increases through glycosylation
First sign of male puberty
Testicular enlargement
Important neuropeptides/proteins/metabolic factors responsible for rise in GnRH with puberty
Stimulatory: NPY (controversial), Glutamate, Kisspeptin, Tachykinins (Neurokinin B, TACR3/TAC3), Leptin, Insulin,
Inhibitory: GABA, MKRN3, Ghrelin
Premature puberty definition
Signs of secondary sexual development occurring before the age of eight years in girls and the age of nine years in boys are considered premature and warrant careful evaluation
How to differentiate between central and peripheral premature puberty
GnRH Stim test
• High LH after stim -> gonadotropin dependent (central)
• Low/normal LH after stim -> gonadotropin independent (peripheral)
Central (gonadotropin-dependent) premature puberty etiologies
90% idiopathic
CNS lesions
Previous excess sex steroid exposure
Pituitary gonadotropin-secreting tumors
Secondary component of McCune-Albright syndrome
Poorly controlled CAH
Central premature puberty treatment
GnRH agonist
Central premature puberty genetics
- Gain-of-function mutations in kisspeptin 1 gene (KISS1) and its receptor (KISS1R)
- Loss-of-function mutation in MKRN3 (imprinted gene in Prader-Willi critical region)
- Loss-of-function mutation in DLK1 (delta-like 1 homolog)
CNS lesions leading to central premature puberty
Hamartomas, CNS tumors, CNS radiation
Peripheral (gonadotropin-independent) premature puberty etiologies in females (2)
Ovarian cysts – most common Ovarian tumors (Granulosa cell \> Sertoli/Leydig, pure Leydig, gonadoblastoma)
Peripheral (gonadotropin-independent) premature puberty etiologies in males (3)
Leydig cell tumors
HCG-secreting germ cell tumors
Activating mutation in LH receptor
Inheritance and pathophysiology of activating LH receptor mutation causing peripheral premature puberty
Autosomal dominant; premature Leydig cell maturation and testosterone secretion
Presentation of activating LH receptor mutation causing peripheral premature puberty in boys
Precocious puberty with normal spermatogenesis but arrested
Presentation of activating LH receptor mutation causing peripheral premature puberty in girls
Girls are not affected clinically, because (similar to hCG-secreting germ tumors) activation of both the LH and FSH receptors is required for estrogen biosynthesis
Treatment of activating LH receptor mutation causing peripheral premature puberty
Androgen receptor antagonist (spironolactone) and aromatase inhibitor
Peripheral (gonadotropin-independent) premature puberty etiologies in males and females
- Primary hypothyroidism (also associated with delayed bone age)
- Exogenous sex steroids/endocrine disruptors
- Adrenal pathology
- McCune-Albright syndrome
McCune-Albright syndrome genetics and pathophysiology
Somatic mutation of the alpha subunit of the Gs protein (GNAS) that activates adenylyl cyclase
Constitutively active adenylate cyclase converting ATP to cAMP
cAMP activates protein kinase A
Cause of precocious puberty = ovarian follicular cysts
McCune-Albright syndrome presentation
Triad of peripheral precocious puberty, irregular café-au-lait (“coast of Maine”) skin pigmentation, and fibrous dysplasia of bone
McCune-Albright syndrome treatment 1st option, 2nd option, & how to treat fibrous dysplasia of bone
(drugs that block aromatization and estrogen production)
Aromatase inhibitor - reduce the potential for compromised adult height due to early epiphyseal fusion from sustained estrogen exposure and reduce recurrent vaginal bleeding, but effect fades over time
Tamoxifen
If develop gonadotropin-dependent component due to chronic estrogen exposure, can use GnRH agonist
Bisphosphonates used to treat fibrous dysplasia of bone
Premature pubarche definition
Isolated appearance of sexual hair (ie, sexual hair without breast development in girls, or without testicular enlargement in boys) before the age of eight years in girls and nine years in boys
Premature pubarche etiology
Usually premature adrenarche; others: CAH, cushing’s, androgen secreting tumor
Testing for etiology of premature pubarche
Bone age = single most important test (detect accelerated skeletal maturation/evidence of early virilization)
- If normal, likely idiopathic/not severe cause -> repeat bone age in 6 months
- If advanced, determine if bone age is proportionally advanced for child’s height
• If normal for height, virilizing disorder unlikely
• If advanced for height -> DHEAS, testosterone -> 17-OHP -> ACTH stim test
Premature adrenarche definition
Very mild form of hyperandrogenism that is a variant of normal: it causes a slowly progressive, incomplete form of premature puberty; requires biochemical demonstration of a serum steroid pattern indicative of adrenarche before eight in girls and before nine in boys
Testing for premature adrenarche
o DHEAS = best marker for presence of adrenarche (level > 40mcg/dL)
o If ACTH stim test performed, DHEA +/- 17OH-pregnenolone are typically increased for age
& bone age
Premature thelarche definition
o Isolated breast development, either unilateral or bilateral – typically not developing beyond Tanner stage 3
o Absence of other secondary sexual characteristics
o Normal height velocity for age (not accelerated)
o Normal or near-normal bone age
Presentation of premature thelarche (timing)
Most cases of premature thelarche are idiopathic and present under two years of age (and may even start at birth).
Indications for treatment of precocious puberty
o Predicted height below target
o Growth velocity > 6 cm/year
o Progression to next stage of development (thelarche, pubarche, menarche) in 3-6 months
o Bone age advance > 1 year or more
Treatment monitoring in precocious puberty
Monitoring treatment (q3-6 months): Height measurement, bone age, serum LH levels < 3 IU/L
Delayed puberty definition
Absence or incomplete development of secondary sexual characteristics bounded by an age at which 95 percent of children of that sex and culture have initiated sexual maturation
- 12 years for girls (breast development being the first sign, Tanner stage B2)
- 14 years for boys (increase in testicular size being the first sign, Tanner stage G2)
- Pubarche not usually included in this definition because typically a sign of adrenarche, rather than true puberty
Etiologies of delayed puberty
Primary (hypergonadotropic) hypogonadism (43%):
• Abnormal karyotype (26%): Turner’s, Klinefelter
• Normal karyotype/ovarian failure (17%)
Secondary (hypogonadotropic) hypogonadism (31%): [alpha subunit def]
• Constitutional delay of growth and puberty (10%)
• Isolated GnRH deficiency (Kallman’s)
• Other forms of hypo-hypo (poor nutrition, chronic disease, hypothyroid, excessive exercise)
• Hypothalamic or pituitary disease (tumors, esp craniopharyngioma; prolactinoma, injury, etc)
Eugonadism (26%): MRKH (14%), septum, hymen, AIS
Presentation of inactivating LH receptor mutation in males
Azoospermia 2/2 leydig cell hypoplasia
Presentation of inactivating LH receptor mutation in girls
Primary amenorrhea (hypo/hypo), with normal breast/hair
Sequence of hormone rise in puberty out of (in alphabetical order):
- Andrenal androgens
- Estradiol
- FSH
- Leptin
- LH
- Adrenal androgens
- Leptin
- FSH
- LH
- Estradiol
What contributes to timing of peak growth velocity?
Sex steroid-induced increase in GH secretion
Best predictor of menarche?
Weight / Body fat %
Role of leptin in puberty?
Produced by?
Acts as a metabolic signal to trigger onset of puberty
Produced by adipocytes – serum levels associated with body fat content
How does one determine the absence of the vas deferens?
Physical exam
If isolated thelarche/pubarche/adrenarche - do you need to treat?
what if cysts present?
No, as long as bong age appropriate and no other signs of pubertal development
Cysts ok as well - form from intermittent pulsatile FSH
What causes precocious puberty but DELAYED bone age?
Hypothyroidism
Bone age
When to do it?
What is scanned?
1st step in precocious puberty eval
Single x-ray of left hand/fingers/wrist
What is testolactone and what is it used to treat?
Antineoplastic agent – derivative of progesterone
Inhibits steroid aromatase activity
Used to treat:
Advanced breast cancer
McCune-Albright syndrome (loses effectiveness over time)
Older teen with primary amenorrhea and no secondary sex characteristics (prepubertal)
Best test?
FSH
Older teen with primary amenorrhea and only breast development.
Best test?
Testosterone
What causes clitoromegaly?
excess androgens
Most likely cause of virilization at puberty?
5α-reductase deficiency (type 2)
No DHT in embryogenesis, but regular testosterone is made at puberty, and 5α-reductase Type 1 is able to make some DHT at puberty
Which enzyme defect is associated with sexual infantilism (& HTN)?
17α-hydroxylase
