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Delayed Puberty – A Disorder in Timing???? Kristy Parker PGY-2 Pediatrics December 4 th, 2009.

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Presentation on theme: "Delayed Puberty – A Disorder in Timing???? Kristy Parker PGY-2 Pediatrics December 4 th, 2009."— Presentation transcript:

1 Delayed Puberty – A Disorder in Timing???? Kristy Parker PGY-2 Pediatrics December 4 th, 2009

2 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.

3 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

4 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

5 History Review of Systems CNS: visual changes/visual field abnormalities, headaches, anosmia Cardiac: congenital anomaly Respiratory: asthma Renal: GI: diarrhea, blood in stools

6 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


8 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]testicularml 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 [ ] Tanner IV testicular volume between 12 and 20 ml; scrotum enlarges further and darkens; penis increases in length to 10 cm and circumference [ ] Tanner V testicular volume greater than 20 ml; adult scrotum and penis of 15 cm in length [14+]


10 Tanner Pubic Staging Pubic hair (both male and female) Tanner I no pubic hair at all (prepubertal Dominic state) [typically age 10 and younger]prepubertal 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]penisscrotumlabia majora 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]pubis Tanner V hair extends to medial surface of the thighs [15+]

11 Tanner Breast Development Breasts (female) Tanner I no glandular tissue; areola follows the skin contours of the chest (prepubertal) [typically age 10 and younger]areola Tanner II breast bud forms, with small area of surrounding glandular tissue; areola begins to widen [ ] breast bud 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 [ ] Tanner IV increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast [13-15]papilla Tanner V breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. [15+]


13 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


15 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

16 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

17 Age of Pubertal Progression Females Thelarche Generally considered the onset of puberty Occurs in most girls at Menarche Mean age of onset = 12 yrs Adrenarche Usual onset at approx age 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)

18 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

19 Pubertal Progression Males Gonadarche Testicular enlargement generally heralds the onset of puberty (testes > 4ml). This usually starts around 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

20 Pubertal Milestones FemalesMales Tanner stage 2 breastsTesticular growth Tanner stage 2 pubic hairTanner 2 genital development Peak linear growthTanner stage 2 pubic hair Greatest weight gainTanner stage 3 genital Tanner stage 3 breastTanner stage 3 pubic hair Axillary hair growthPeak linear growth AcneOnset of pubertal gynecomastia MenarcheAxillary hair Tanner stage 4 breastVoice pitch changes Tanner stage 4 pubic hairAcne Tanner stage 5 breastSpermarche Regular menstrual cyclesTanner stage 4 genital Tanner stage 5 pubic hairTanner stage 4 pubic hair Tanner stage 5 pubic hair Tanner stage 5 genital


22 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

23 Psychological Effects 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


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

26 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.

27 Pubertal Delay 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

28 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

29 Pubertal Delay Hypogonadotropic Hypogonadism Hypergonadotropic Hypogonadism Eugonadotropic Hypogonadism Low FSH, LH Low sex steroids High FSH, LH Low sex steroids Normal FSH, LH

30 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%

31 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

32 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

33 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)

34 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


36 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

37 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

38 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

39 Syndromes Associated with Pubertal Delay Prader-Willi syndrome Laurence Moon syndrome Septo-optic dysplasia Bardet-Biedl syndrome

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

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

42 Hypergonadotropic hypogonadism Gonadal damage secondary to chemotherapy/radiation Enzyme defects in the gonads Androgen insensitivity Ovarian/testicular dysgenesis (causes of gonadal failure)

43 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)

44 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 % are infertile More female type fat distribution Tall in childhood, with euchanoid body habitus Have fathered children (particularly those with mosaicism)


46 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

47 Turner syndrome cont’d… Residual ovarian function can cause breast development in 15-25%, menarche in 5-10% & pregnancy in 1-3%


49 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

50 Eugonadotropic pubertal delay Congenital Anatomic Anomalies Imperforate hymen Vaginal atresia Vaginal aplasia PCOS Hyperprolactinemia

51 In this case, secondary sex characteristics are normal May have cyclic lower abdominal pain

52 Chronic Illness Can affect underlying genetic potential May limit adequate nutrition (ie. inflammatory bowel disease, cystic fibrosis) May be associated with glucocorticoid use, chemotherapy or radiation

53 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**

54 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

55 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 Clinical And Endocriological Metabolism

56 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

57 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

58 Androgen Supplementation Testosterone IM Injections (once puberty has begun) Doses of mg 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

59 hCG Can also use to stimulate development of secondary sexual characteristics Increases testicular size Can be used to stimulate fertility units qalt days

60 Stimulating Puberty in Females 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

61 Estrogen Replacement in Females Initiate replacement at age 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)

62 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

63 Estrogen Side Effects Thromboembolism Endothelial dysfunction Hyperlipidemia Increased risk of breast & gynecological malignancy Increased risk of gallstones

64 Achieving Fertility May require pulses of GnRH in females hCG in males 1-2 times/week helps to maintain spermatogenesis IU hCG IM 3 times weekly hMG IM 3 times weekly

65 References Ambler, G.R. Androgen Therapy for Delayed Male Puberty. Current Opinion in Endocrinology : 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 (8): Delemarre, E.M., Felius, B., and H.A. Delemarre-van de Waal. Inducing Puberty. European Journal of Endocrinology : 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 : Hindmarsh, P.C. How do Initiate Oestrogen Therapy in a Girl who has not Undergone Puberty? Current Endocrinology : Normal Pubertal Development. Lee, P.A. and Kulin, H.E. Pediatric Endocrinology: The Requisites pg Rosen, D.S. and C. Foster. Delayed Puberty. Pediatrics in Review Vol 22 (9): pg Kulin, H.E. and J. Muller. The Biological Aspects of Puberty. Pediatrics in Review Vol 17 (3) Mirsa, M. and M. M. Lee. Delayed Puberty. Pediatric Endocrinology. The Requisites pg Sperling, M. Pediatric Endocrinology Puberty and Its Disorders in the Female. Pg

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