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Delayed Puberty – A Disorder in Timing????. Kristy Parker PGY-2 Pediatrics December 4 th , 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.

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Delayed puberty a disorder in timing

Delayed Puberty – A Disorder in Timing????

Kristy Parker

PGY-2 Pediatrics

December 4th, 2009


Canmeds objectives
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
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
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
History

  • Review of Systems

    • CNS: visual changes/visual field abnormalities, headaches, anosmia

    • Cardiac: congenital anomaly

    • Respiratory: asthma

    • Renal:

    • GI: diarrhea, blood in stools


Physical examination
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 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
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
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
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 physiology1
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
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
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 changed

    • Differences between ethnic groups

    • ? Related to environmental factors or food additives

    • ? Related to better nutritional status, increased body mass/adiposity


Pubertal progression
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



http://psycnet.apa.org/journals/bul/110/1/images/bul_110_1_47_fig2a.gifhttp://psycnet.apa.org/journals/bul/110/1/images/bul_110_1_47_fig2a.gif


Role of bone age
Role of Bone Agehttp://psycnet.apa.org/journals/bul/110/1/images/bul_110_1_47_fig2a.gif

  • 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
Psychological Effectshttp://psycnet.apa.org/journals/bul/110/1/images/bul_110_1_47_fig2a.gif

  • Puberty occurs during adolescence during time of identity formation

  • Period of increased physical changes

  • When 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
Pubertal Delay adrenal gland & HPG axis for gonadotropin secretion

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

  • Pubertal delay is most often seen in males

    • Present far more often than females as delay causes more significant psychosocial implications

  • Most commonly no pathology present


Timing of puberty
Timing of Puberty adrenal gland & HPG axis for gonadotropin secretion

  • 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 delay1
Pubertal Delay adrenal gland & HPG axis for gonadotropin secretion

Pubertal Delay

Hypogonadotropic

Hypogonadism

Hypergonadotropic

Hypogonadism

Eugonadotropic

Hypogonadism

Low FSH, LH

Low sex steroids

High FSH, LH

Low sex steroids

Normal FSH, LH


Pubertal delay2
Pubertal Delay adrenal gland & HPG axis for gonadotropin secretion

  • 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
Hypogonadotropic Hypogonadism adrenal gland & HPG axis for gonadotropin secretion

  • 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
Constitutional Delay of Puberty adrenal gland & HPG axis for gonadotropin secretion

  • 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
Constitutional Delay of Puberty cont’d… adrenal gland & HPG axis for gonadotropin secretion

  • 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 d1
Constitutional Delay of Puberty cont’d… adrenal gland & HPG axis for gonadotropin secretion

  • 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
Kallman Syndrome adrenal gland & HPG axis for gonadotropin secretion

  • 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
Idiopathic Hypogonadotropic hypogonadism adrenal gland & HPG axis for gonadotropin secretion

  • 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
Excessive exercise adrenal gland & HPG axis for gonadotropin secretion

  • 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
Syndromes Associated with Pubertal Delay adrenal gland & HPG axis for gonadotropin secretion

  • Prader-Willi syndrome

  • Laurence Moon syndrome

  • Septo-optic dysplasia

  • Bardet-Biedl syndrome


Panhypopituitarism
Panhypopituitarism adrenal gland & HPG axis for gonadotropin secretion

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


What controls the timing adrenal gland & HPG axis for gonadotropin secretion

of puberty? An update

on progress from genetic

investigations? Current

Opinion in Endocrinology. 2009


Hypergonadotropic hypogonadism
Hypergonadotropic hypogonadism adrenal gland & HPG axis for gonadotropin secretion

  • Gonadal damage secondary to chemotherapy/radiation

  • Enzyme defects in the gonads

  • Androgen insensitivity

  • Ovarian/testicular dysgenesis (causes of gonadal failure)


Gonadal failure bilateral
Gonadal Failure (bilateral) adrenal gland & HPG axis for gonadotropin secretion

  • 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
Klinefelter’s Syndrome adrenal gland & HPG axis for gonadotropin secretion

  • 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
Turner Syndrome adrenal gland & HPG axis for gonadotropin secretion

  • 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
Turner syndrome cont’d… adrenal gland & HPG axis for gonadotropin secretion

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


Receptor defects
Receptor Defects adrenal gland & HPG axis for gonadotropin secretion

  • 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
Eugonadotropic pubertal delay adrenal gland & HPG axis for gonadotropin secretion

  • Congenital Anatomic Anomalies

    • Imperforate hymen

    • Vaginal atresia

    • Vaginal aplasia

  • PCOS

  • Hyperprolactinemia



Chronic illness
Chronic Illness adrenal gland & HPG axis for gonadotropin secretion

  • Can affect underlying genetic potential

  • May limit adequate nutrition (ie. inflammatory bowel disease, cystic fibrosis)

  • May be associated with glucocorticoid use, chemotherapy or radiation


Other endocrine causes
Other Endocrine Causes adrenal gland & HPG axis for gonadotropin secretion

  • 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
Investigating Delayed Puberty adrenal gland & HPG axis for gonadotropin secretion

  • 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
Psychological Distress in Pubertal Delay adrenal gland & HPG axis for gonadotropin secretion

  • 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 Clinical

And Endocriological Metabolism. 2006.


Stimulating puberty in males
Stimulating Puberty in Males adrenal gland & HPG axis for gonadotropin secretion

  • 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 adrenal gland & HPG axis for gonadotropin secretion

    • 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
Androgen Supplementation adrenal gland & HPG axis for gonadotropin secretion

  • 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


  • hCG adrenal gland & HPG axis for gonadotropin secretion

    • Can also use to stimulate development of secondary sexual characteristics

    • Increases testicular size

    • Can be used to stimulate fertility

    • 200-500 units qalt days


Stimulating puberty in females
Stimulating Puberty in Females adrenal gland & HPG axis for gonadotropin secretion

  • Estrogen Replacement

    • Increased gradually to adult replacement levels (as puberty is normally a slow process)

    • Aims:

      • Attainment of secondary sexual characteristics

      • Attainment of menses

      • Stimulation of pubertal growth spurt

      • Acquisition of bone mineral mass

      • Uterine development


Estrogen replacement in females
Estrogen Replacement in Females adrenal gland & HPG axis for gonadotropin secretion

  • 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 adrenal gland & HPG axis for gonadotropin secretion

    • 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
Estrogen Side Effects adrenal gland & HPG axis for gonadotropin secretion

  • Thromboembolism

  • Endothelial dysfunction

  • Hyperlipidemia

  • Increased risk of breast & gynecological malignancy

  • Increased risk of gallstones


Achieving fertility
Achieving Fertility adrenal gland & HPG axis for gonadotropin secretion

  • May require pulses of GnRH in females

  • hCG in males 1-2 times/week helps to maintain spermatogenesis

    • 1200-5000 IU hCG IM 3 times weekly

    • 12.5-150 hMG IM 3 times weekly


References
References adrenal gland & HPG axis for gonadotropin secretion

  • 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.


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