Delayed Puberty

Delayed Puberty
Dr. Shinjan Patra

Outline
• Definition and causes
• Constitutional Delay in Growth and
Puberty (CDGP)
• Hypogonadotropic Hypogonadism
Kallmann syndrome (IHH)
Other forms of IHH
Genetics of IHH
Differentiation with CDGP
Chronic systemic diseases and CNS
tumors
• Hypergonadotropic Hypogonadism
Klinefelter’s
Turner’s
Radiation and chemotherapy
Others
• Diagnostic approach
History/Examination/Lab Studies
/Genetics
Algorithm
• Treatment

Introduction
• Puberty leads to sexual maturation and reproductive capability
• Requires an intact HPG axis and heralded by the reemergence of
GnRH secretion from its relative quiescence during childhood
• Factors that trigger pubertal onset remain elusive
• Late puberty can affect psychosocial well-being for patients and
families
• May affect adult stature

Definition of Delayed puberty
• The upper limits of the normal age of onset of puberty are 2 SD above the
mean
• 14 years for boys (although some sources say 13.5 years) and 13 years for
girls
• Due to downward trend in pubertal timing and differences among racial
and ethnic groups, currently researchers advocating lower age cut off
• Divided into disorders that affect the operation of the GnRH pulse
generator, the pituitary gland or the gonad
Aksglaede L, Sørensen K, Petersen JH, Skakkebaek NE, Juul A. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 2009;123(5): e932-e939
Sørensen K, Aksglaede L, Petersen JH, Juul A. Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J Clin Endocrinol Metab 2010;95:263-70.

Howard and Dunkel Delayed Puberty Endocrine Reviews, October 2019, 40(5):1285–1317

Important causes
CDGP
Hypo Hypo
CNS
tumors/inflam
mations
Isolated
Gonadotropin
deficiency
(Kallmann)
Functional
Gonadotropin
deficiency
Hyper Hypo
Males
Females
Klinefelter's Chemo/Rad
io/Trauma
Turners Chemo/R
T/Autoiim
une/PCO
S

Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med. 2012;366:443–453

Pubertal Timings and it’s determinants

CDGP/Idiopathic
• Most common diagnosis for delayed puberty
• Usually short (2 SD below the mean value of height for age) at evaluation
•
• Shorter than their classmates for years
• Growth velocity and height usually appropriate for bone age
• Family history in as many as 77% of cases reveals a mother who had delayed
menarche or a father (or sibling) who entered puberty late
• 2% oligogenicity compared to 15% oligogenicity in CHH subjects
• Mutations in immunoglobulin superfamily member 10 (IGSF10) found in males
Varimo T, Miettinen PJ, K¨ans¨akoski J, Raivio T, Hero M. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a
large patient series from a single tertiary center. Hum Repro 2017;32(1):147–153

Patho-physiology
• Mutations appear to inhibit the normal migration of the neurons
• Physiologic immaturity with a slow tempo of maturation
• Full sexual maturity takes longer than usual
• Adrenarche and gonadarche occur later
• Generally achieve sexual maturation by 18 years of age
Wehkalampi K, Wid´en E, Laine T, Palotie A, Dunkel L. Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to
specialist pediatric care. J Clin Endocrinol Metab. 2008;93(3):723–728

Anthropometry
• Thin, but 25% above the 85th percentile in BMI for age
• Heavier boys have less delayed bone age than classic thin patients
• Heavier individuals reach greater height than thinner
• Greater increased total energy expenditure (TEE) per kilogram fat-free mass
(FFM)
• First signs of secondary sexual development occur within 1 year after LH rises to
pubertal levels in response to administration of intravenous synthetic GnRH or
subcutaneous GnRH agonist
Winter S, Ousidhoum A, McElreavey K, Brauner R. Constitutional delay of puberty: presentation and inheritance pattern in 48 familial cases. BMC Pediatr. 2016;16:37

Diagnostic dilemma
• More common in boys
• No single test reliably distinguishes between CDP and IHH, watchful
waiting the only way
• Temporary state of functional GH insufficiency

Isolated Hypogonadotropic hypogonadism
• Defect involving the GnRH pulse generator or gonadotrophs without an
anatomic lesion
• Prepubertal concentration of gonadal sex steroid values and low serum
gonadotropin levels or values within the normal range
• Pulsatile LH secretion often virtually absent
• LH response to GnRH or GnRH agonist administration deficient in the
severe form
• IHH may occur in families (about 20–30% of patients) or sporadically
Sidhoum VF, Chan YM, Lippincott MF, et al. Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system. J Clin
Endocrinol Metab. 2014;99(3):861–870

Anthropometry
• Height appropriate for age
• Estradiol too low to cause epiphyseal fusion at the normal age,
increased arm span for height and a decreased ratio of upper to lower
body segments (i.e., eunuchoid body proportions)
• Poor spine growth due to delay in exposure to gonadal steroids
• About 22% of affected patients with IHH and severe delay of puberty
spontaneously increase their testicular size and enter full puberty

Other features
• Micropenis and/or cryptorchidism
• Primary amenorrhea
• Severely reduced TV (<4 mL)
• Sparse facial and body hair
• High-pitched voice
• Steady linear growth without a growth spurt
• Final height rarely affected
• Delayed bone age
• Erectile dysfunction
• Infertility
• Osteopenic fractures
Jacques Young et al. Clinical Management of Congenital Hypogonadotropic Hypogonadism. Endocrine Reviews 40: 669 – 710, 2019

Kallmann syndrome
• Most common form of IHH
• Diminished or absence of nocturnal pulses of gonadotropins
• Classically presents with undescended testes along with micropenis
• Anosmia or hyposmia resulting from agenesis or hypoplasia of the olfactory
lobes or sulci
• Loss of olfaction usually correlates with the degree of GnRH deficiency
• Testing with graded dilutions of pure scents necessary to determine partial
anosmia
• Prevalence 1 of every 10,000 males and 1 of every 40,000 females
Kallmann F, Schonfeld W, Barrera S. Genetic aspects of primary eunuchoidism. Am J Ment Defic. 1944;48:203–236

GnRH neurons & its anatomic abnormality
• Unusual neuronal population, as they originate outside the central nervous system
• Follows the axon guidance of the vomeronasal nerve (VNN) and the olfactory nerve
• Complete transition around 15 weeks of gestation
• In KS, do not migrate from the olfactory placode to the medial basal hypothalamus
• End in a tangle around the cribriform plate and in the dural layers adjacent to the
meninges beneath the forebrain
Schwarting GA, WiermanME, Tobet SA. Gonadotropinreleasing hormone neuronal migration. Semin Reprod Med. 2007;25(5):305–312

Other defects
• Cleft lip
• Cleft palate
• Unilateral or rarely bilateral renal aplasia or dysplasia
• Mirror movements of the upper extremities (i.e., bimanual synkinesia)
• Imperfect facial fusion
• Seizure disorders
• Short metacarpals
• Pes cavus
• Neurosensory hearing loss
• Cerebellar ataxia and nystagmus
• Ocular motor abnormalities
Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T. Incidence, phenotypic features and molecular genetics of Kallmann syndrome in
Finland. Orphanet J Rare Dis. 2011;6(1):41

Types
KAL1 KAL2 KAL3
Classic X-linked Autosomal dominant Autosomal recessive
ANOSM1 (previously KAL1), FGF17,
IL17RD, DUSP6, SPRY4, and FLRT3:
oligogenic in nature
FGFR1 PROKR2
Synkinesia Dental agenesis and skeletal
abnormalities
Hearing loss
Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T. Incidence phenotypic features and molecular genetics o Kallmann syndrome in Finland. Orphanet J Rare Dis
2011;6(1):41

Other forms of IHH
Disease Features Puberty
GnRH mutation Very rarely reported Form of Normosmic IHH
GnRHR mutation C/F heterogenous Various degrees of familial and
sporadic hypogonadotropic
hypogonadism with normosmia
KISS/KISSR mutation Plays a role in the increased amplitude of GnRH
signaling in puberty
Decreased secretion of GnRH and
decreased response to GnRH
administration
Adrenal Hypoplasia
congenita
XR; Mutation in DAX1
Severe glucocorticoid, mineralocorticoid and
androgen deficiency
Typically presents with
Hypogonadotropic hypogonadism
Isolated LH deficiency Deficient testosterone production Responds to hCG administration
Isolated FSH
deficiency
Immunoactive FSH absent Primary amenorrhea
Men have azoospermia
Septo-Optic dysplasia Abnormal development of the prosencephalon
Optic hypoplasia or dysplasia
Midline hypothalamic defect
Short stature and delayed puberty

Jacques Young et al. Clinical Management of Congenital Hypogonadotropic Hypogonadism. Endocrine
Reviews 40: 669 – 710, 2019

Harrington J, Palmert M. Distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. J Clin
Endocrinol Metab. 2012;97:3056–67

To differentiate CDGP & IHH
CDGP IHH
Presenting manifestations Growth failure and delayed puberty Delayed puberty
Family history Strong Occasional
Neonatal manifestations Absent Typically cryptorchidism and micropenis
Anosmia/Neurological Mx Absent Very Likely
Height Velocity Normal Normal
Pubarche Delayed Normal/delayed
Testicular volume > 4 ml < 4 ml
Final Adult height Within range of TH Exceeds TH
GnRH-stimulated LH response May be normal Blunted
Wehkalampi K, Wid´en E, Laine T, Palotie A, Dunkel L. Patterns of inheritance of constitutional delay of growt and puberty in families of adolescent girl and boys referred to specialist pediatric
care. J Cli Endocrinol Metab. 2008;93(3):723–728

Basal serum Τ >50 ng/dl is evidence of the onset of puberty
In those with serum Τ <50 ng/dl our data suggest that a single injection of
HCG 15 IU/kg, with serum Τ determined 48 hours later (> 170 ng/dl), is more
discriminatory and offers the most reliable, easy to perform, least painful, and by far the
most cost effective test

Assessed the accuracy of the GnRH agonist test (triptorelin 0.1 mg) in comparison with inhibin B alone or
in combination with basal LH for the diagnosis of IHH
Basal LH <0.3 IU/l, stimulated LH (4 h) <5.3 IU/l or inhibin B <111 pg/ ml had 100% sensitivity for IHH
Only LH (4 h) <5.3 IU/l had a specificity of 100%, and the specificities of basal LH <0.3 IU/l (88%) or inhibin
B <110 pg/ml (92%) were lower
Combinations increased the specificity to 98%
Measurement of inhibin B and basal LH in combination is a valid, reliable and less-invasive alternative test

Usefulness of markers of gonadal activity, growth axis activation and adrenarche differentiation between
pre-pubertal CDGP and HH
Inhibin B and AMH were higher in boys with PP CDGP than in boys with HH: inhibin B: 87.6 +/- 42.5 vs.
19.8 +/- 13.9 pg/mL; p < 0.001; AMH: 44.9 +/-27.1 vs. 15.4 +/- 8.3 ng/mL; p < 0.001
ROC for the diagnosis of PPCDGP vs. HH (inhibin B ≥ 28.5 pg/mL): sensitivity: 95%, specificity: 75%; AUC:
0.955
In combination with an AMH cut-off ≥20 ng/mL the specificity increased to 83%
INSL3, IGF1, IGFBP3 and DHEAS levels were not different

IHH reversal
• Previously considered as a lifelong condition
• Reversibility occurs in both male and female (10% to 20% in males, and a
few case reports for females)
• No clear clinical factors for predicting reversible
• An enrichment of TAC3/TAC3R mutations observed in one series of patient
• Demonstrated the plasticity of the GnRH neuronal system
• Treatment with sex steroids was the only common denominator
• Recovery may not be permanent
Dwyer AA, Raivio T, Pitteloud N. Management of endocrine disease: reversible hypogonadotropic hypogonadism. Eur J Endocrinol. 2016;174(6): R267–R274

Pradar Will Syndrome
Basic features Early-onset childhood hyperphagia, pathologic obesity
Phenotypical
features
Almond shaped eyes
Triangular mouth
Narrow bifrontal diameter
Short stature
Brachydactyly
Puberty Hypogonadotropic hypogonadism caused by combined hypothalamic and gonadal
dysfunction
Hormonal Alteration FSH high normal
LH normal
Serum AMH low normal
Inhibin B levels consistently low or undetectable
Others Genomic imprinting

Laurence-Moon and Bardet-Biedl Syndromes
• Hypogonadism characteristic and both male and female leading to
infertility
• Basic defect ciliopathy
• Developmental delay
• Spastic paraplegia
• Postaxial polydactyly
• Onset of obesity usually in early infancy
• Renal dysplasia

Chronic systemic diseases
Malnutrition Weight loss from any cause to less than 80% of ideal weight for height; weight regain usually
restores hypothalamic-pituitary gonadal function
Cystic fibrosis Determined by nutritional status ; Oligospermia
Sickle cell disease At least delayed by 6 months to 2 years; mostly due to nutritional status
Boys show impaired Leydig cell function caused by ischemia of the testes or gonadotropin deficiency
Thalassemia • Secondary hemochromatosis related ; 60% to 80% can have hypogonadotropic hypogonadism
• Satisfactory sexual development can be promoted by hcG/FSH
• Cytotoxic agents usage in BMT can add to the problem
HIV infection Significantly delayed ; modern t/t decrease the delay
Celiac disease Normal puberty can be achieved with proper diet
CKD • Decreased pulsatile gonadotropin secretion due to a decrease in the mass of bioactive and
immunoactive LH secreted rather than an alteration of the frequency
• Successful renal transplantation cures it
• Also immunosuppressive medications can delay it
Leukemia Receiving radiation therapy can severely impair central gonadal axis
Chatterjee R, Mukhopadhyay TN, Chandra S, Bajoria R. Sex steroid priming for induction of puberty in thalassemia patients with pulsatile reversible hypogonadotrophic
hypogonadism. Hemoglobin. 2011;35(5–6):659–664

Other endocrine conditions
• Hypothyroidism (uncontrolled )
• Type 1 Diabetes ( specially Mauriac syndrome )
• Pediatric Cushing’s syndrome

Anorexia Nervosa
• Amenorrhea, low E2/FSH/LH (central suppression of the HPG axis)
• Low BMI and low leptin
• Hormonal alteration
• Excessive exercise
• Reversion to sleep-associated increase in episodic LH secretion or LH
response to GnRH characteristic of early puberty
• Pulsatile administration of intravenous GnRH at intervals of 90 to 120
minutes can produce LH pulses that are indistinguishable from the
normal pubertal pattern

Exercise induced
• Thinness and strenuous physical activity appear to act synergistically,
itself inhibit the GnRH pulse generator
• With normal weight who have less fat and more muscle than
nonathletic girls are also at risk for delayed puberty and for primary
and secondary amenorrhea

Craniopharyngioma
Basic features M/C brain tumor associated with hypothalamic-pituitary dysfunction and sexual infantilism
Phenotypical
features
Headache
Visual disturbances
Short stature
DI
Puberty Typically associated with arrested puberty
T/t Combination of limited tumor removal and radiation therapy leads to a satisfactory
neurologic prognosis
Keil MF, Stratakis CA. Pituitary tumors in childhood: update of diagnosis, treatment and molecular genetics. Expert Rev Neurother. 2008;8(4):563–574

Germinoma
Basic features Most common extrasellar tumors that arise in the suprasellar hypothalamic region
Phenotypical features DI followed by visual difficulties and abnormalities of growth
Abnormal movements
Puberty Typically delayed or arrested puberty
T/t Combination of chemotherapy and radiation

Pituitary adenoma
• 2% to 6% of all surgically treated pituitary tumors occur in childhood
and adolescence, with about 1 in 1 million children affected
• Delayed puberty quite common in prolactinoma
• Medical T/t usually suffices

Langerhans cell histiocytosis
• Infiltration of lipid-laden histiocytic cells or foam cells in skin, viscera,
and bone
• Cystlike areas in flat and long bones and the DL spine may be involved
• DI, GH deficiency and delayed puberty usual features
• Treatment with glucocorticoids, antineoplastic agents and radiation
therapy promising in terms of survival
• >50% of patients have late sequelae or disease progression

KS and it’s variants
Basic features Seminiferous tubule dysgenesis , Approximately 1 in 1000 males
Small, firm testes (usually <3.5 cm)
Impaired spermatogenesis
Anthropometry Decreased U/L body ratio without an increase in arm span rather than eunuchoid
proportions
Puberty Onset may not be delayed, but impaired Leydig cell reserve and low testosterone levels
may lead to slow progression or arrest of pubertal changes
Hormonal alteration Normal increase in the T, INSL3 and inhibin B before puberty
Mid-puberty T and INSL3 concentrations remain low-normal range
AMH levels undetectable
LH and FSH usually rise by mid-puberty
Christiansen P, Andersson AM, Skakkebaek NE. Longitudinal studies of inhibin B levels in boys and young adults with Klinefelter syndrome. J Clin Endocrinol Metab.
2003;88(2):888–891

TS and it’s variants
Basic features Short stature and sexual infantilism
Phenotypical
features
Micrognathia, Fishmouth appearance, High-arched palate with dental abnormalities
Epicanthal folds, ptosis
Broad, shieldlike chest
Short fourth metacarpals
Cubitus valgus
Extensive pigmented nevi, Keloid formation, Hypoplastic nails
Coarctation of the aorta in about 10%, aortic stenosis, and bicuspid aortic valves
Intestinal telangiectasias and hemangiomatoses
IBD
Hashimoto thyroiditis
Puberty 10% of cases, puberty, menarche and (rarely) pregnancy may occur
Pubertal growth spurt absent
Bondy CA. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007;92(1):10–25

Cancer chemotherapy
• Irradiation of the gonads or the use of alkylating chemotherapeutic
agents
• COPP/MOPP chemotherapy for Hodgkin disease can cause severe
damage to Sertoli and germinal cells, less effect on Leydig cells
• ABVD regimen can cause germ cell depletion
van den Berg H, Furstner F, van den Bos C, Behrendt H. Decreasing the number of MOPP courses reduces gonadal damage in survivors of childhood Hodgkin disease. Pediatr Blood Cancer.
b2004;42(3):210–215

Radiation therapy
• Direct radiation doses of more than 2 Gy will likely impair
spermatogenesis
• Preservation of sperm by freezing being investigated for pediatric
cancer patients (Onco-fertility)
• 30 Gy carries a recurrence rate of 6 for ovarian insufficiency
• Ethical and logistics problems
Ginsberg JP, Carlson CA, Lin K, et al. An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety. Hum Reprod.
2010;25(1):37–41

Anorchia Cryptorchidism
• Undescended testis rate in term/ AGA babies 1.0% to 4.6%, whereas in
premature/SGA infants 1.1% to 4.3%
• Serum gonadotropins follow the normal U-shaped curve of high values in
infancy and puberty with lower values in mid-childhood
• Serum AMH and inhibin B nondetectable
• Germ cell maturation hampered
• Postpubertal orchidopexy is associated with a greater than 85% prevalence
of azoospermia or oligospermia
• Successful fertilization by ICSI
Lee PA, Coughlin MT. Fertility after bilateral cryptorchidism. Evaluation by paternity, hormone, and semen data. Horm Res. 2001;55(1):28–32

SGA
• Predisposes males to reproductive problems
• Smaller testes and lower testosterone and higher LH levels
• Increased aromatase and 5α-reductase activities, leading to elevated
levels of estradiol and dihydrotestosterone
Cicognani A, Alessandroni R, Pasini A, et al. Low birth weight for gestational age and subsequent male gonadal function. J Pediatr. 2002;141(3):376–379

Autoimmune Oophoritis
• Ovarian failure leading to primary amenorrhea, oligomenorrhea, arrest of
puberty, and occasionally cystic enlargement of the ovaries
• Most often associated with other autoimmune endocrinopathies,
especially autoimmune Addison disease, in which it may precede the onset
of adrenal insufficiency
• Ab to cytochrome P450 steroidogenic enzymes
• Glucocorticoid therapy may improve, at least temporarily, ovarian function
• Among APS-1, 36% of women manifest ovarian failure before age 20 , only
4% men manifest hypogonadism that early

LH resistance
• Autosomal recessive disorder caused by a mutation in LHCGR
• Gene locus : 2p21
• Impaired secondary sexual development (pre-pubertal testis)
• Gynecomastia
• Primary Amenorrhea
• Elevated plasma LH levels
• Early pubertal plasma T that did not increase after hCG administration

Homozygous galactosemia
• Mutation in the galactose-1-phosphate uridylyltransferase (GALT)
• Primary ovarian failure, from failure to develop puberty to primary or
secondary amenorrhea and premature menopause
• Pathogenesis remains unclear but probably involves galactose itself
and its metabolites, such as galactitol and uridine diphosphate
galactose
• Dietary restriction programs have not prevented the ovarian failure
Rubio-Gozalbo ME, Gubbels CS, Bakker JA, et al. Gonadal function in male and female patients with classic galactosemia. Hum Reprod Update. 2010;16(2):177–188

Haploinsufficiency of FOXL2 gene
• Rare autosomal dominant disorder involving eyelid dysplasia and
premature ovarian failure
• Small palpebral fissures, ptosis, and a small skinfold extending inward
and upward from the lower lid
• Ovarian failure varies from primary amenorrhea to irregular menses
and premature ovarian failure
Crisponi L, Deiana M, Loi A, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/ epicanthus inversus syndrome. Nat Genet.
2001;27(2):159–166

Noonan syndrome
• Features that differentiate these individuals from those with Turner syndrome include
 Triangular facies
 Pectus excavatum
 Right-sided heart disease (e.g., pulmonary stenosis, often with valve dysplasia; atrial septal defect)
 Hypertrophic cardiomyopathy
 Varied blood clotting defects
 Increased incidence of developmental delay
• Autosomal dominant
• About 1/3rd boys and girls enter delayed puberty
Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noon an syndrome. Lancet. 2013;381(9863):333–342

Whom to include also
• Boy who has not completed secondary sexual maturation within 4.5
years after onset of puberty
• Girl who does not menstruate within 5 year after onset

Important medical history
• Puberty failed to occur or did it begin but failed to progress or even
regress
• Details pertaining to growth and development
• Birth history
• Similar family history
• Symptoms of chronic or intermittent illnesses
• Patient’s sense of smell
• Parental consanguinity

Physical examination
• Anthropometric measurements
• Growth chart plotting
• Height velocity for last 12 months
• U/L ratio
• Arm span and relationship with height
• SMR
• Examination of the optic discs and visual fields
• Olfaction
• CVS and other systems

Differentiation
Hypo Hypo
 Cryptorchidism , Micropenis and
small soft testis
 Eunuchoidal proportions
 Typical Neurological abnormality
like Anosmia, synkinesia, midline
defects
 Virilisation largely absent
Hyper Hypo
 Small firm testis
 Long-leggedness (KS)
 Absent
 Moderate degree present

Lab studies
• Testo/Estradiol/LH/FSH
• Inhibin B /AMH
• BA
• TFT
• Prolactin
• US evaluation of pelvis
• Semen analysis
• Karyotype
• MRI Brain/pituitary ( including olfactory bulb)
• GnRH stimulation test
• Genetic testing ( KAL1/CHD7/PCSK1)
• BMD DXA

Olfaction
• Using semiquantitative methods such as the UPSIT score or the Sniffin
Sticks tests
• Give age- and sex-matched scores relative to a reference population
• Volatile-stimulated chemosensory evoked potentials can be used
• Continuum rather than a binary classification
Lewkowitz-Shpuntoff HM, Hughes VA, Plummer L, Au MG, Doty RL, Seminara SB, Chan YM, Pitteloud N, Crowley WF Jr, Balasubramanian R. Olfactory phenotypic spectrum in
idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications. J Clin Endocrinol Metab. 2012; 97(1):E136–E144
Maione L, Cantone E, Nettore IC, Cerbone G, D Brasi D, Maione N, Young J, Di Somma C, Sinisi AA Iengo M, Macchia PE, Pivonello R, Colao A. Flavo perception test: evaluation in
patients with Kallman syndrome. Endocrine. 2016;52(2):236–243.

Assessment of the newborns
• Micropenis and/or cryptorchidism at birth
• Low sex steroid and gonadotropin levels in an infant <3-6 months of
age indicate central hypogonadism with absence of the normal mini-
puberty
• Inhibin B for male infants
• AMH in female infant

CDGP
• Mostly assurance
• For psychologic reasons, for boys 14 years old or older who show no
signs of puberty, a 3-month to 6-month course of testosterone
enanthate, cypionate, or cyclopropionate
• 50-mg dose given intramuscularly every 4 weeks
• Short-acting preparations are advisable
• Usually one to two course of therapy sufficient

Intervention: Receive either six intramuscular injections of low-dose testosterone (about 1 mg/kg
bodyweight) every 4 weeks for 6 months or peroral letrozole 2∙5 mg once daily for 6 months
Results: During treatment, boys in the letrozole group had higher serum concentrations of LH/FSH/T and
inhibin B than did boys in the testosterone group
Testicular growth from baseline to 6 months was greater in the letrozole group than in the testosterone
group ; between-group difference per month 0∙9 mL [95% CI 0∙6–1∙2], p<0∙0001

In this study 8 patients with CDGP underwent treatment with Lz (2.5 mg/day) for a year, and 8 patients with
CDGP, who did not receive Lz were followed up to reaching final height
The final heights for Lz group were significantly (p=0.04) higher than the control group

Letrozole superior to placebo but not T in regards to PAH after 12 months of use
Lz superior to Placebo + T in regards to TV
Lz superior to T in regards to slowing of bone age
LH/FSH/T/Inhibin B significantly higher in Lz compared to T

Hypogonadotropic hypogonadism
• Choice between sex steroids and gonadotropins
• Low-dose gonadal steroids by age 14 in boys and age 13 in girls, regardless
of the definitive diagnosis of gonadotropin deficiency
• Microphallus due to hypothalamic deficiencies may be treated with one or
two 3-month courses of testosterone enanthate (25 mg/month)
• Pulsatile GnRH therapy can induce puberty and promote the development
of secondary sexual characteristics and spermatogenesis in men and
ovulation in women
• Pregnancy can be achieved

Compared the pubertal effects of human chorionic gonadotropin (hCG) versus testosterone in adolescent
males with HH
Parameters: Mean testicular volume (MTV), penile length, growth velocity and testosterone levels
Mean T/t duration: 14 months
MTV higher in hCG group
Rest didn’t differ
hCG potentially improve future fertility outcomes

Hypergonadotropic hypogonadism
• Gonadal dysgenesis: E2 therapy should be initiated when the patient is age 13
(bone age >11 years) to allow secondary sexual development at an appropriate
chronologic age
• 17-b Estradiol patches (0.05–0.1 μg/kg in younger girls or 0.08–0.12 μg/kg in
older girls every night)
• Progestational agents may be initiated as 5 to 10 mg of progesterone first given 5
days per month increasing to 14 days per month toward adulthood
• Testosterone therapy in Klinefelter’s : Injectable/dermal therapy ; dose of 10 mg
of 2% transdermal testosterone given for 6 months achieved similar effects to 50
mg of intramuscular testosterone in terms of height velocity

Take home message
• Proper clinical evaluation at the outset is necessary to determine the
etiology of delayed puberty
• Judicious lab based investigations to be carried out
• CDGP definitely the most prevalent cause (but a diagnosis of
exclusion)
• Basal LH + Inhibin B/Inhibin B + AMH is a good option compared to
GnRH stimulation test along with clinical history to differentiate with
HH
• Fertility achievement in IHH is to be done by proper GnRH pulse
therapy or hCG administration

Delayed Puberty

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