Delayed pubertyLaura Tatpati, MD – Clinical Associate Professor – University of Kansas SOM - Wichita

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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

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

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

Step 3 Labs

Step2

Exam

Step1History

History

• Birth hx

• Developmental hx

• Family hx/Family developmental/pubertal hx

• ROS• GI/GU/Endocrine/Neuro

• PMH• Incl. Prior systemic therapies

Classification by exam:Short stature

• Underlying genetic cause suspected

• Endocrinopathy

• GH deficiency

• Thyroid deficiency

• Hypopituitarism

Used by Henry Turner in his 1938 publication

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)

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?

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

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)

A few diagnoses to review

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

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

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

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)

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)

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

Primary Amenorrhea Review

Williams Gyn Ch. 16

Thank You!

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