Delayed Puberty – A Disorder in Timing????

Kristy ParkerPGY-2 PediatricsDecember 4th, 2009

CanMEDS Objectives

Medical Expert 1. Outline the normal physiology, progression, and timing of

pubertal development.

2. Delineate causes of delayed puberty in both the male and female.

3. Explain how to differentiate between constitutional delay and other causes of delayed puberty.

Manager 1. Outline appropriate investigations for male and female

patients with delayed puberty.

Assessment of Puberty

History Parents

Important to ask about onset of puberty in parents Menarche (more reliable in mothers as they remember onset) Male growth spurt (as most fathers recall their pubertal progression

more vaguely) Age of first shaving regularly

Parental heights (identify midparental height) “late bloomer” vs. “early bloomer”

Body changes? (important to ask about EACH) Thelarche (galactorrhea) Adrenarche/pubarche (body odor, axillary & pubic hair, acne) Menarche Gonadarche

History cont’d…

Important to include: Past medical history (history of brain tumor,

radiation, chemotherapy, known genetic disorder, chronic disease affecting growth)

Eating habits Any evidence of disordered eating

Activity level Is exercise excessive or is this an athlete with a high level

of training

Growth history Previous growth chart can be extremely helpful

History

Review of SystemsCNS: visual changes/visual field

abnormalities, headaches, anosmiaCardiac: congenital anomalyRespiratory: asthmaRenal:GI: diarrhea, blood in stools

Physical Examination

Examination of Growth Height Weight Head circumference Upper to lower segment ratios

Pubertal Assessment (Tanner staging) Axillary hair Pubic hair & staging Breast development & staging Genital development & staging

Neurological assessment

CPS position statement on growth measurment

Tanner Staging of Puberty in Males

Tanner I  prepubertal (testicular volume less than 3.5 ml; small penis of 3 cm

or less) [typically age 9 and younger] Tanner II 

testicular volume between 1.6 and 6 ml; skin on scrotum thins, reddens and enlarges; penis length unchanged [9-11]

Tanner III  testicular volume between 6 and 12 ml; scrotum enlarges further;

penis begins to lengthen to about 6 cm [11-12.5] Tanner IV 

testicular volume between 12 and 20 ml; scrotum enlarges further and darkens; penis increases in length to 10 cm and circumference [12.5-14]

Tanner V  testicular volume greater than 20 ml; adult scrotum and penis of 15

cm in length [14+]

Tanner Pubic Staging

Pubic hair (both male and female) Tanner I 

no pubic hair at all (prepubertal Dominic state) [typically age 10 and younger]

Tanner II  small amount of long, downy hair with slight pigmentation at the base

of the penis and scrotum (males) or on the labia majora (females) [10–11.5]

Tanner III  hair becomes more coarse and curly, and begins to extend laterally

[11.5–13] Tanner IV 

adult-like hair quality, extending across pubis but sparing medial thighs [13–15]

Tanner V  hair extends to medial surface of the thighs [15+]

Tanner Breast Development

Breasts (female) Tanner I 

no glandular tissue; areola follows the skin contours of the chest (prepubertal) [typically age 10 and younger]

Tanner II  breast bud forms, with small area of surrounding glandular tissue; areola

begins to widen [10-11.5] Tanner III 

breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with surrounding breast [11.5-13]

Tanner IV  increased breast size and elevation; areola and papilla form a secondary

mound projecting from the contour of the surrounding breast [13-15] Tanner V 

breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. [15+]

Normal Pubertal Physiology

- HPG axis (hypothalamic-pituitary-gonadal) is essential in turning on puberty at appropriate times

- Pulsatile secretion of GnRH is essential - GnRH is produced in hypothalamus (in

arcuate nucleus)- GnRH travels to the anterior pituitary to

stimulate the production of LH & FSH

Normal Pubertal Physiology

HPG axis is active in the first few weeks of life LH & FSH rise as hCG from placenta is gone This results because the fetoplacental unit acts to produce

negative feedback on the HPG axis during late gestation HPG axis usually quiescent during childhood

Result of negative feedback on the hypothalamus Axis re-stimulated during adolesence

Stimulation results in a positive feedback loop (estrogen from maturing follicle stimulates LH surge for ovulation)

Pulsatile release of hormone increases overnight first. This eventually progresses to secretion during day and night. LH can be detected in pulsatile forms. FSH has longer half-life, so pulses not as evident

Menarche does not signal full maturation of HPG axis (may simply be withdrawl bleeding from progesterone -> cycle takes longer to become ovulatory

Role of Gonadotropins

FSH Stimulates androstenedione by the ovary Involved in spermatogenesis in the testes Induces receptors for LH

LH Uses androstenedione for substrate to produce

estradiol in theca cells Stimulates testosterone synthesis by Leydig cells

FSH is usually higher than LH in prepubertal stages, and this reverses in pubertal stages

Age of Pubertal Progression

Females Thelarche

Generally considered the onset of puberty Occurs in most girls at 9.5-10.4

Menarche Mean age of onset = 12 yrs

Adrenarche Usual onset at approx age 9.4-10.6 yrs

Linear Growth Generally occurs before Tanner Stage 2 breast development Generally adds 20-25cm of height in females GH increases during puberty as well (provides 50% of growth

spurt)

(NHANES III dates)

Are females entering puberty earlier?Onset of puberty earlier, but completion has

not changedDifferences between ethnic groups? Related to environmental factors or food

additives? Related to better nutritional status,

increased body mass/adiposity

Pubertal Progression

Males Gonadarche

Testicular enlargement generally heralds the onset of puberty (testes > 4ml). This usually starts around 10.8-11.1 yrs.

Initial increases in testicular size are due to increase in Sertoli (supporting cells)

Average time to complete genital development = 3yrs Thelarche

2/3 of males will have gynecomastia develop during puberty (midpubertal)

Gynecomastia results from direct testicular secretion of estrogen as well as peripheral conversion of prohormones to estrogen

Pubarche Linear growth

Peak growth generally occurs after Tanner Stage 5 Generally adds 25-30cm in height for males

Pubertal MilestonesFemales MalesTanner stage 2 breasts Testicular growth

Tanner stage 2 pubic hair Tanner 2 genital development

Peak linear growth Tanner stage 2 pubic hair

Greatest weight gain Tanner stage 3 genital

Tanner stage 3 breast Tanner stage 3 pubic hair

Axillary hair growth Peak linear growth

Acne Onset of pubertal gynecomastia

Menarche Axillary hair

Tanner stage 4 breast Voice pitch changes

Tanner stage 4 pubic hair Acne

Tanner stage 5 breast Spermarche

Regular menstrual cycles Tanner stage 4 genital

Tanner stage 5 pubic hair Tanner stage 4 pubic hair

Tanner stage 5 pubic hair

Tanner stage 5 genital

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Role of Bone Age

Comparing radiographs of hand & wrist to reference standards

Female skeletal maturity is generally 2 yrs advanced as compared to males

Pubertal events more correlated with bone age than chronological age

Psychological Effects

Puberty occurs during adolescence during time of identity formation

Period of increased physical changesWhen teens are behind their peers in

terms of development, can lead to substantial teasing/bullying & self-esteem issues

Jameson, J.L. Rites of passage through puberty: A complex genetic ensemble. PNAS.October 30, 2007. Vol 104, No. 44.

NR0B1 gene is involved in development & function of the adrenal gland & HPG axis for gonadotropin secretion

GPR54 gene mutations affect GnRH release (these patients do respond to exogenous GnRH)

PROP1 mutations lead to problems in differentiation of gonadotropicc, somatotropic, lactotropic & thyrotropic cells.

Pubertal Delay

Based on statistical norms (>2 SD from the population mean)

Pubertal delay is most often seen in malesPresent far more often than females as

delay causes more significant psychosocial implications

Most commonly no pathology present

Timing of Puberty

Consider pubertal delay if: No breast development by age 13 in a female No menses by age 15 in a female Testicular size < 2.5cm or 4mL or pubic hair is not

present by age 14 in a male Consider precocious puberty if:

Breast development before age 8 or menarche before age 10 in females

Testes volume > 3ml before 9 years. Pubic hair development before 8 years in females,

and 9 years in males

Pubertal Delay

Pubertal Delay

Hypogonadotropic Hypogonadism

HypergonadotropicHypogonadism

EugonadotropicHypogonadism

Low FSH, LHLow sex steroids

High FSH, LHLow sex steroids

Normal FSH, LH

Pubertal Delay

Sedlmeyer et al. identified in their study that delayed puberty in men could be classified as Constitutional delay of growth & puberty in

63%Delay associated with underlying medical

condition 20%Hypogonadotropic hypogonadism 9%Hypergonadotropic hypogonadism 7%

Hypogonadotropic Hypogonadism

Constitutional Delay of Puberty Malnutrition Excessive Exercise Growth Hormone Deficiency Isolated Gonadotropin Deficiency Endocrine Causes Miscellaneous syndrome complexes Brain tumors

Craniopharyngioma, astrocytomas, gliomas, histiocytosis X, germinomas, prolactinomas

Iron overload (pituitary damage) GnRH receptor abnormalities

Constitutional Delay of Puberty

Most common cause of pubertal delay Delayed puberty often found in siblings or

parents Diagnosis of exclusion Bone age is delayed & consistent with degree

of pubertal maturation (usually delayed by 2yrs or more

Often associated with constitutional short stature

Constitutional Delay of Puberty cont’d…

Progressive height gain, but along lower limits of normal (contrast to isolated gonadotropin deficiency which has normal growth, but no pubertal growth spurt)

Early morning testosterone levels > 0.7nmol/L predict puberty within 15 months (Wu et al)

Constitutional Delay of Puberty cont’d…

Differentiated by pathological gonadotropin deficiency by observation over time (no definitive test available) GnRH stimulation test occasionally used, but not

conclusive HPG axis responds to GnRH more strongly if it has

already been exposed to this (reflects previous stimulation)

hCG stimulation test can also be undertaken (Degros et al)

Stimulated testosterone < 3 nmol/L suggestive of hypogonadotropic hypogonadism

Stimulated testosterone >9 nmol/L suggestive of CDGP

Kallman Syndrome

A syndrome of isolated gonadotropin deficiency

1/10,000 males, 1/50,000 females Present with ANOSMIA or HYPOSMIA Can be difficult to differentiate from

constitutional delay KAL-1 gene encodes protein (anosmin)

required for GnRH neurons to migrate from olfactory placode to cribiform plate

Can also be associated with harelip, cleft palate, and congenital deafness

Idiopathic Hypogonadotropic hypogonadism

Males often have eunochoid body proportions (upper-to-lower segment ratio of < 1)

Can be sporadic or familial Can be related to problems in the receptor for

GnRH Can present as infant with micropenis &

cryptorchidism. These infants will not show normal gonadotropin increase in the first few weeks of life

Excessive exercise

Questions as to whether lack of puberty related to low body weight or more as a direct effect of exercise Interruption of training in ballet dancers,

runners

Syndromes Associated with Pubertal Delay

Prader-Willi syndromeLaurence Moon syndromeSepto-optic dysplasiaBardet-Biedl syndrome

Panhypopituitarism

Pubertal delay is usually not presentation (present with short stature earlier)

What controls the timing of puberty? An update on progress from genetic investigations? Current Opinion in Endocrinology. 2009

Hypergonadotropic hypogonadism

Gonadal damage secondary to chemotherapy/radiation

Enzyme defects in the gonadsAndrogen insensitivityOvarian/testicular dysgenesis (causes of

gonadal failure)

Gonadal Failure (bilateral)

In these cases, circulating levels of LH & FSH are high (hypergonadotropic hypogonadism)

Congenital Turner Syndrome Klinefelter’s Syndrome Complete androgen insensitivity

Acquired Chemotherapy/Radiation/Surgery Postinfectious (ie. mumps orchitis, coxsackievirus infection, dengue,

shigella, malaria, varicella) Testicular torsion Autoimmune/metabolic (autoimmune polyglandular syndromes) “Vanishing Testes syndrome” “Resistant Ovaries syndomre” (gonadatropin receptor problems)

Klinefelter’s Syndrome

45 XXY most common (2/3), remainder are mosaic or variant Many affected boys will not be identified until adolescence when

puberty is delayed Some pubertal development, but testes eventually become

fibrotic Timing relates to degree of mosaicism in the patient

Small testicles & gynecomastia Also often small phallus size 90-100% are infertile More female type fat distribution Tall in childhood, with euchanoid body habitus Have fathered children (particularly those with mosaicism)

Turner Syndrome

45 XO genotype most common Associated with short stature, variable degrees of

puberty, primary amenorrhea & multiple congenital anomalies

Often presenting complaint is short stature, but in others, may present with delayed puberty

Most have primary ovarian failure 50% of patients have some breast develpoment,

some axillary/pubic hair is typical for most patients Associated with SHOX mutations which cause the

short stature

Turner syndrome cont’d…

Residual ovarian function can cause breast development in 15-25%, menarche in 5-10% & pregnancy in 1-3%

Receptor Defects

LH gene defects and FSH gene defects can result in high levels of FSH & LH with low sex steroids

Secondary sex characteristics are driven by LH effects, can have FSH receptor defect & normal secondary sex characteristics

Eugonadotropic pubertal delay

Congenital Anatomic Anomalies Imperforate hymenVaginal atresiaVaginal aplasia

PCOSHyperprolactinemia

In this case, secondary sex characteristics are normal

May have cyclic lower abdominal pain

Chronic Illness

Can affect underlying genetic potentialMay limit adequate nutrition (ie.

inflammatory bowel disease, cystic fibrosis)

May be associated with glucocorticoid use, chemotherapy or radiation

Other Endocrine Causes

Hypothyroidism Interferes with gonadotropin secretion

(affects pulsatile secretion of LH)

Hyperprolactinemia Interfere with gonadotropin production

**prolactinomas may not always be visible on imaging**

Investigating Delayed Puberty

Investigations depend on clinical presentation, but may include Bone age Hormone levels (IGF-1, FSH, LH, estradiol,

testosterone, DHEAS, prolactin, TSH) Karyotype Hormone stimulation tests

GnRH stimulation test GH stimulation test

Imaging MRI if gonadotropins high & no obvious cause of

hypogonadotropic hypogonadism

Psychological Distress in Pubertal Delay

Much has been written about psychological distress in males with delayed puberty

Self-Esteem & Sexuality in girls with Turner Syndrome has been studied Generally had low self-esteem scores (general & social) Lifetime sexual experience associated with overall SEI score Increasing sexual experience had no effect (all-or-none

phenomenon) Ross et al. -> initiation of estrogen therapy associated with

increased self-esteem in girls with Turner syndrome

Psychosocial Adjustment in Turner Syndrome. Journal of ClinicalAnd Endocriological Metabolism. 2006.

Stimulating Puberty in Males

Should be begun at 12yrs of age Multiple indications For CDGP

Indicated in those boys with psychological distress (who have poor body image, low self-esteem, are becoming socially withdrawn, or are subjected to teasing or bullying)

Time of therapy initiation may vary (if GH deficiency present, delay starting to optimize height achievement)

Testosterone supplementation may help with bone mineral density

Exogenous testosterone Does not increase testicular size (normal puberty continues

to progress) Causes virilization (increased phallic size & scrotal rugae) Accelerates development of secondary sex characteristics

to avoid psychosocial complications Should be used only if bone age is delayed, and

introducted at approx. normal time of development Also stimulates growth spurt Side effects

Local discomfort at site of injection priapism

Androgen Supplementation

Testosterone IM Injections (once puberty has begun)

Doses of 50-200mg IM using testosterone esters have been used for periods of 6-12 months

Depot testosterone like this results in high testosterone peaks & a duration of action of 2-3 weeks

Theoretic advantage for negative feedback on HPG axis to be alleviated with “wearing off” of exogenous testosterone

Oral Associated with more gradual effects Testosterone undecanoate 40mg po qdaily Oxandrolone 2.5mg po qdaily

Gels, transdermal patches, etc. have not been studied as well in boys & dosing is less predictable

hCGCan also use to stimulate development of

secondary sexual characteristics Increases testicular sizeCan be used to stimulate fertility200-500 units qalt days

Stimulating Puberty in Females

Estrogen Replacement Increased gradually to adult replacement

levels (as puberty is normally a slow process)

Aims:Attainment of secondary sexual characteristicsAttainment of mensesStimulation of pubertal growth spurtAcquisition of bone mineral massUterine development

Estrogen Replacement in Females

Initiate replacement at age 10-12 yrs & should continue over course of normal puberty (approx. 3 yrs)

Effect of estrogen on growth plate is dose dependent Higher doses stimulate epiphyseal growth plate closure

Once dose of 10-15mcg of ethinyloestradiol has been reached, breakthrough bleeding becomes apparent – once this occurs, progesterone should be added on a cyclic basis to prevent endometrial hyperplasia

Dosing 0.3mg conjugated estrogen daily 5mcg of ethinyl estradiol daily Transdermal estrogen 25mcg twice weekly Increase q6-12 months until maximum (20 mcg)

Suggested dosing increments Ethinyloestradiol

2mcg/day X 6 months 4 mcg/day X 6 months 6 mcg/day X 6 months 10 mcg/day X 6 months 15 mcg/day X 6 months

17-estradiol 5mcg/day po 10 mcg/day po 15 mcg/day po 20 mcg/day po

Introduce progesterone once breakthrough bleeding has occurred, after this point can switch to an oral contraceptive pill

Estrogen Side Effects

ThromboembolismEndothelial dysfunctionHyperlipidemiaIncreased risk of breast & gynecological

malignancyIncreased risk of gallstones

Achieving Fertility

May require pulses of GnRH in femaleshCG in males 1-2 times/week helps to

maintain spermatogenesis1200-5000 IU hCG IM 3 times weekly12.5-150 hMG IM 3 times weekly

References

Ambler, G.R. Androgen Therapy for Delayed Male Puberty. Current Opinion in Endocrinology. 2009. 16: 232-239.

Carel, J., Elie, C., Ecosse, E., Tauber, M., Leger, J., Cabrol, S., Nicolino, M., Brauner, R., Chaussain, J, and J. Coste. Self-Esteem and Social Adjustment in Young Women with Turner Syndrome – Influence of Pubertal Management and Sexuality: Population-Based Cohort Study. The Journal of Clinical Endocrinology & Metabolism. 2006. 91 (8): 2972-2979.

Delemarre, E.M., Felius, B., and H.A. Delemarre-van de Waal. Inducing Puberty. European Journal of Endocrinology. 2008. 159: S9-S15.

Gajdos, Z.K.Z., Hirschhorn, J.N. and M.R. Palmert. What controls the timing of puberty? An update on progress from genetic investigation. Current Opinion in Endocrinology, Diabetes & Obesity. 2009. 16: 16-24.

Hindmarsh, P.C. How do Initiate Oestrogen Therapy in a Girl who has not Undergone Puberty? Current Endocrinology. 2009. 71: 7-10.

Normal Pubertal Development. Lee, P.A. and Kulin, H.E. Pediatric Endocrinology: The Requisites. 2005. pg 63-71.

Rosen, D.S. and C. Foster. Delayed Puberty. Pediatrics in Review. 2001. Vol 22 (9): pg 309-315.

Kulin, H.E. and J. Muller. The Biological Aspects of Puberty. Pediatrics in Review. 1996. Vol 17 (3)

Mirsa, M. and M. M. Lee. Delayed Puberty. Pediatric Endocrinology. The Requisites. 2005. pg. 87-101

Sperling, M. Pediatric Endocrinology. 2008. Puberty and Its Disorders in the Female. Pg 530-609.