city berlin design...how does that help us? •a large percentage can be identified early by a...
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Delayed pubertyLaura Tatpati, MD – Clinical Associate Professor – University of Kansas SOM - Wichita
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No disclosures
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Delayed puberty : defined
• 2.5 SD from the mean
• Age 13 without thelarche
• Age 15 without menarche (16 is 3SD)
• ACOG/AAP rec eval also if:• Menarche absent w/in 3 y of thelarche (T4 breasts @ menarche) typical• Menarche absent @ 14 w/ hirsutism or history or exam suggest disordered
eating/excessive exercise or outflow abnormality
• Earlier eval appropriate if hx/px suggest potential problem !
Reindollar et al. 2015
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Delayed puberty : etiologies
• Ovarian insufficiency 43%• Turner 26%
• 46XX 15% 46XY 2%
• CAUV 14%
• Constitutional delay 10%
• Constitutional 30%
• Ovarian insufficiency 26%• Turner 7%
• 46XX 17% and 46XY 2%
• Permanent hypo hypo 20%• Kallmann's, Idiopathic, anatomic lesions,
panhypopit, craniopharyngioma
Some others: PCOS 7%, IHH 7%, eating d/o, systemic illness,giardia, RA, SLE,
Sickle cell, hypothyroidism, GH defic, Hyperprolactinemia, CAH, cushing, Prl, Cong
heart dz, Seizure d/o
Reindollar et al. 2015
Georgia 1981 Boston 2002
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How does that help us?
• A large percentage can be identified early by a couple of things• Growth Chart plotting
• Elevated FSH or testosterone
• Physical exam inspecting introitus
• Outlier:• IHH – diagnosis of exclusion in late teenage years
• Constitutional Delay• < 1/3 in both series!
• 2/3 evaluated have pathology!!
Reindollar et al. 2015
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Step 3 Labs
Step2
Exam
Step1History
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History
• Birth hx
• Developmental hx
• Family hx/Family developmental/pubertal hx
• ROS• GI/GU/Endocrine/Neuro
• PMH• Incl. Prior systemic therapies
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Classification by exam:Short stature
• Underlying genetic cause suspected
• Endocrinopathy
• GH deficiency
• Thyroid deficiency
• Hypopituitarism
Used by Henry Turner in his 1938 publication
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Classification by exam:Breast development
No = Hypoestrogenism
• Ovarian failure
• HPO immaturity
• HPO suppression
• Steroidogenesis defect
Yes = Normal Estrogen Milieu (at one time at least)
• CAUV/MRKH
• PCOS/chronic anovulation
• DSD/Intersex – ex. androgen insensitivity
• 13-30% w/ Turner Syndrome have thelarche +/- menarche (2-5%) (incl. Mosaics)
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Estrogen +/-
• Breast development – one time or persistent estrogen presence
• Persistent estrogen signs• Estradiol (serum)
• Progestin challenge
• Endometrium 1.5mm or greater
• Cervical mucus
• Vaginal smear - > 15% superficial cells
• Others?
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Classification by exam:Pubic Hair +/-
• After 13, absence or sparse is likely pathological• **Breast & introitus
examination is useful
• HPO delay does not typically impact HPA function
• Suspect:
• Pituitary Insufficiency . (46XX)
• Steroidogenesis disorder (46XX or 46XY)
• 17-hydroxylase deficiency
• Hypertension/Hypokalemia (incr DOC/corticosterone)
• 46XX --> lack pubic hair, breasts and have female int/ext organs
• 46XY --> lack pubic hair, breasts and have ambiguous genitalia and internal male organs
• Androgen receptor disorder (46XY)
• AIS
• 46XY --> normal breast development, blind pouch; "male" T level
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Classification by exam:Introitus: Vagina +/- (Blind pouch)
• Examination, not karyotype, is most cost-effective initial screen• Bulging introitus
• Imperforate hymen
• Bulging mid-line mass on rectal examination or ultrasound
• Transverse vaginal septum
• Uterus on rectal examination or ultrasound
• Congenital absence of vagina
• No uterus or bulging mass
• Pubic hair + or -/sparse
• + = CAUV
• -/sparse = AIS
• No uterus/vagina, no breasts, no pubic hair --> 46 XY 17 hydroxylase deficiency (CAH)
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A few diagnoses to review
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Androgen insensitivity syndrome
• 1 in 20,000 females dx at birth
• ? 1.1% of those w/ inguinal hernias
• X-linked recessive (androgen receptor sequencing possible)
• Functional testes (not dysgenetic)
• Normal male testosterone level, confirmatory karyotype
• peripheral conversion of T-->E
• AMH secreted leads to absence of mullerian system (MIS)
• 2% gonadoblastoma risk so leave in until after puberty at least --> referral to DSD specialty clinic advised
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5 a Reductase deficiency
• Autosomal recessive mutation
• Ext female genitalia or ambiguous genitalia or micropenis/hypospadius
• T DHT
• Male phenotypic changes at puberty may occur
• May change gender role at this time or may not
• 46XX females w/ two mutations are unaffected developmentally
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Mullerian agenesis
• 53% have congenital anomalies• Skeletal, urinary, CV (VACTERL)
• Karyotype is typically 46,XX
• Rearrangements, duplications & deletions/gene mutations can be identified on karyo/microarray (WNT4/WNT9) and some could indicate appropriate screening
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46XY gonadal dysgenesis (Swyer Syndrome)
• Mutation of testicular morphogenesis such as SRY (15%) (other gene mutations as well)• No AMH/MIS --> Mullerian development occurs
• No androgens --> female external genitalia
• Elevated FSH at puberty
• Highest risk of germ cell tumor of streak gonads
• Surgically excise at dx (non-functional, no reason to keep d/t risk)
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Constitutional Delay
• Not the norm for females (60% males delay is constitutional)
• FH of delayed puberty is common
• Bone age lags
• Later thelarche typical
• Low / Normal gonadotropins
• Most difficult to differentiate btwn this and IHH • (no puberty by 18 confirms this but one should not delay exogenous
pubertal development for this)
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TAKE AWAY POINTS
• DELAYED PUBERTY IN FEMALES IS LIKELY PATHOLOGIC
• SO, WORK IT UP!• HISTORY
• PHYSICAL
• BASIC LABS – bhCG (+thelarche), FSH, TSH, Prolactin
• Sparse / absent pubic hair: T, CONFIRMATORY KARYOTYPE IF APPROPRIATE
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Primary Amenorrhea Review
Williams Gyn Ch. 16
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Thank You!
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Resources
• Reindollar, RH, Davis AJ, McLean M. Abnormalities of Female Pubertal Development. Endotext.org
• www.endotext.org : https://www.endotext.org/chapter/abnormalities-of-female-pubertal-development/#toc-an-overview-of-delays-within-the-h-p-o-circuit-delays-of-secondary-sexual-development-and-menarche
• Committee on Adolescent Health Care : The Initial Reproductive Health Visit.Number 598, May 2014 (Replaces Committee Opinion Number 460, July 2010) (Reaffirmed 2018)
• https://www.guttmacher.org/geography/united-states
• ACOG Committee Opinion Number 728, January 2018 (Replaces Committee Opinion Number 562, May 2013) https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Adolescent-Health-Care/Mullerian-Agenesis-Diagnosis-Management-and-Treatment