Delayed or Absent Puberty: Diagnostic Evaluation & Management Tool
Clinical History Assessment
Systematic approach to history taking for a child presenting with delayed or absent puberty
Physical Examination Guide
Systematic approach to examining a child with delayed or absent puberty
Diagnostic Approach
Initial Assessment
For an adolescent presenting with delayed or absent puberty, the initial assessment should include:
- Detailed history focusing on growth patterns, timing of pubertal milestones, and family history
- Complete physical examination including Tanner staging and anthropometric measurements
- Assessment of nutritional status and overall health
- Review of growth charts and plotting of height velocity
Diagnostic Criteria for Delayed Puberty
Definitions of delayed puberty:
| Sex | Definition | Key Features |
|---|---|---|
| Girls | No breast development (Tanner stage 2) by age 13 years | Or no menarche by age 15 years, or >5 years from onset of breast development to menarche |
| Boys | No testicular enlargement (≥4 mL or Tanner stage 2) by age 14 years | Or >5 years from onset to completion of genital development |
| Both | Arrested puberty | Lack of progression of pubertal development for >1 year |
Differential Diagnosis
| Classification | Conditions | Features |
|---|---|---|
| Constitutional Delay of Growth and Puberty (CDGP) |
- Normal variant of growth - Delayed bone age - Functional hypogonadotropic hypogonadism |
- Family history of delayed puberty - Normal pre-pubertal growth velocity - Bone age delayed - Eventual spontaneous puberty - Normal hormonal testing (except transient) |
| Hypogonadotropic Hypogonadism (Central) |
- Congenital GnRH deficiency (Kallmann syndrome, idiopathic) - CNS tumors (craniopharyngioma, germinoma) - Hyperprolactinemia - Functional (athletics, anorexia, chronic illness) |
- Low FSH/LH and sex steroids - May have anosmia (Kallmann) - Neurological symptoms (tumors) - History of excessive exercise or weight loss - Associated pituitary deficiencies |
| Hypergonadotropic Hypogonadism (Primary) |
- Turner syndrome (45,X0) - Klinefelter syndrome (47,XXY) - Gonadal dysgenesis - Autoimmune gonadal failure - Post-chemotherapy/radiation |
- Elevated FSH/LH - Low sex steroids - Dysmorphic features (Turner, Klinefelter) - Short stature (Turner) - History of cancer treatment - Other autoimmune conditions |
| Chronic Diseases |
- Inflammatory bowel disease - Celiac disease - Cystic fibrosis - Renal failure - Poorly controlled diabetes |
- Symptoms of underlying disease - Poor weight gain/growth - Functional hypogonadotropic state - Delayed bone age - Other systemic manifestations |
| Endocrinopathies |
- Hypothyroidism - Hyperprolactinemia - Cushing's syndrome - Growth hormone deficiency - Congenital adrenal hyperplasia |
- Specific symptoms of each condition - Abnormal growth patterns - Other hormonal abnormalities - May affect HPG axis secondarily |
Laboratory Studies
Initial laboratory evaluation:
| Investigation | Clinical Utility | Interpretation |
|---|---|---|
| FSH, LH | Distinguish between central and primary hypogonadism | ↑ in primary hypogonadism, ↓ or normal in central hypogonadism |
| Testosterone (males) or Estradiol (females) | Assess gonadal function | Low in both hypogonadotropic and hypergonadotropic hypogonadism |
| Prolactin | Rule out hyperprolactinemia | Elevated in prolactinoma or medications affecting dopamine |
| TSH, Free T4 | Assess thyroid function | Hypothyroidism may cause pubertal delay |
| Complete Blood Count | Screen for chronic disease or inflammation | Anemia, elevated inflammatory markers |
| Comprehensive Metabolic Panel | Assess for chronic disease affecting multiple systems | Renal, liver, nutritional status assessment |
| IGF-1 | Screen for growth hormone deficiency | Low in GH deficiency |
| Bone Age (X-ray of left hand and wrist) | Assess skeletal maturation | Delayed in CDGP and many endocrinopathies |
Advanced Studies
Additional studies based on initial evaluation:
| Investigation | Clinical Utility | When to Consider |
|---|---|---|
| Karyotype | Detect chromosomal abnormalities | Girls with short stature and elevated FSH, boys with small testes and elevated FSH |
| Brain MRI with contrast | Evaluate hypothalamic-pituitary region | Confirmed or suspected central hypogonadism, neurological symptoms, other pituitary deficiencies |
| GnRH stimulation test | Assess hypothalamic-pituitary-gonadal axis | Distinguish CDGP from permanent hypogonadotropic hypogonadism |
| hCG stimulation test (males) | Assess testicular function | Evaluate testosterone production capacity |
| Pelvic/testicular ultrasound | Evaluate gonadal anatomy | Suspected gonadal dysgenesis, ambiguous genitalia, cryptorchidism |
| Genetic testing | Identify genetic causes | Suspected Kallmann syndrome, multiple pituitary deficiencies, family history |
| Celiac screening | Evaluate for celiac disease | Growth delay, gastrointestinal symptoms, family history |
| Growth hormone stimulation tests | Diagnose GH deficiency | Poor growth velocity, delayed bone age, low IGF-1 |
Diagnostic Algorithm
A stepwise approach to diagnosing delayed puberty:
- Confirm delayed puberty based on age and Tanner staging
- Detailed history and physical examination including growth charts and family history
- Bone age assessment to evaluate skeletal maturation
- First-tier laboratory studies: FSH, LH, sex steroids, prolactin, thyroid function, CBC, basic metabolic panel
- Determine pattern: hypogonadotropic vs. hypergonadotropic vs. functional
- Further evaluation based on pattern:
- If hypergonadotropic: karyotype, autoimmune screening, gonadal imaging
- If hypogonadotropic: MRI, specialized genetic testing, evaluation for other pituitary deficiencies
- If suspected CDGP: consider observation with periodic reassessment
- Evaluate for chronic disease if suggested by history or exam
- Consider specialized testing (GnRH stimulation, hCG stimulation) in unclear cases
Management Strategies
General Approach to Management
Key principles in managing delayed or absent puberty:
- Identify and treat underlying cause: Address any primary medical conditions
- Psychosocial support: Address emotional impact and body image concerns
- Sex steroid replacement: Induce secondary sexual characteristics when appropriate
- Regular monitoring: Track development and adjust treatment as needed
- Fertility considerations: Address long-term reproductive implications
Management by Etiology
| Condition | Management Approach | Monitoring and Follow-up |
|---|---|---|
| Constitutional Delay of Growth and Puberty |
- Reassurance and expectant management - Consider short-term sex steroid therapy for psychological support - Nutritional optimization - Re-evaluation every 4-6 months |
- Growth velocity and pubertal progression - Bone age advancement - Psychological adjustment - Expected spontaneous progression |
| Hypogonadotropic Hypogonadism |
- Address underlying cause (tumor removal, weight gain in anorexia) - Sex hormone replacement therapy - Pubertal induction with gradually increasing doses - Consider fertility preservation discussions |
- Secondary sexual development - Bone mineral density - Psychosocial adjustment - Long-term hormone replacement - Fertility options |
| Hypergonadotropic Hypogonadism |
- Sex hormone replacement therapy - Gradual pubertal induction - Address other features of syndrome (e.g., Turner syndrome) - Early discussion of fertility options |
- Secondary sexual development - Bone mineral density - Screening for associated conditions - Psychosocial support - Reproductive counseling |
| Functional Delay (Chronic Disease) |
- Optimize treatment of underlying condition - Nutritional rehabilitation if malnourished - Address energy imbalance in athletes - Consider sex steroid replacement if delay is prolonged |
- Disease activity markers - Nutritional parameters - Pubertal progression - Growth velocity - Bone age advancement |
Sex Hormone Replacement Therapy
| Parameter | Males | Females |
|---|---|---|
| Initial Treatment |
- Testosterone (IM, gel, or patch) - Start at 25-50 mg IM monthly (or equivalent) - Gradually increase every 6 months |
- Estrogen (oral, transdermal) - Start with low dose (oral estradiol 5-10 μg/kg/day) - Increase gradually every 6 months |
| Maintenance Therapy |
- Testosterone 100-200 mg IM every 2 weeks (or equivalent gel/patch) - Adult dose after 2-3 years of therapy |
- After 12-24 months, add cyclic progesterone - Adult dose estrogen with cyclic progesterone - Consider combined oral contraceptive pills |
| Side Effects Monitoring |
- Acne, mood changes - Erythrocytosis - Liver function tests - Lipid profile - Blood pressure |
- Breast tenderness - Nausea - Headache - Thromboembolism risk - Blood pressure |
| Special Considerations |
- Bone age monitoring - Final height predictions - Consider aromatase inhibitors if height concerns - Sperm banking in some cases |
- Bone age monitoring - Uterine development - Transdermal route may be preferred - Egg preservation options |
Fertility Management
| Condition | Fertility Options | Recommendations |
|---|---|---|
| Hypogonadotropic Hypogonadism (Males) |
- Pulsatile GnRH therapy - Gonadotropin therapy (hCG/FSH) - Sperm cryopreservation if possible |
- Often successful with hormone therapy - Testicular volume predicts response - Early discussion of options |
| Hypogonadotropic Hypogonadism (Females) |
- Pulsatile GnRH therapy - Gonadotropin therapy - Oocyte cryopreservation |
- Often successful with hormone therapy - May need controlled ovarian stimulation - Early discussion of options |
| Hypergonadotropic Hypogonadism (Males) |
- Testicular sperm extraction (TESE) - Donor sperm - Adoption |
- Limited options for biological children - Early fertility counseling - Psychological support |
| Hypergonadotropic Hypogonadism (Females) |
- Egg donation - Embryo donation - Adoption |
- Limited options for biological children - Early fertility counseling - Psychological support |
Psychosocial Support
Critical aspects of comprehensive care:
- Address body image concerns: Counseling about developing at a different pace than peers
- Screen for depression and anxiety: Common in adolescents with delayed puberty
- Peer support groups: Connect with others with similar conditions
- Family education: Help parents understand and support their child
- School support: Educate teachers and address potential bullying
Follow-up and Monitoring
| Parameter | Frequency | Assessment |
|---|---|---|
| Physical Growth | Every 3-6 months |
- Height, weight, BMI - Growth velocity - Tanner staging |
| Hormone Levels | Every 6-12 months |
- Sex steroids (testosterone/estradiol) - Gonadotropins (LH/FSH) - Other relevant hormones |
| Bone Health | Baseline and every 1-2 years |
- Bone age X-ray - DEXA scan for bone mineral density - Calcium and vitamin D levels |
| Psychosocial | Every visit |
- Mood assessment - School performance - Social adjustment - Body image concerns |
When to Refer
- Pediatric endocrinologist: Initial diagnosis and management
- Geneticist: Suspected genetic syndromes or family history
- Reproductive endocrinologist: Fertility concerns and preservation
- Mental health professional: Significant psychological distress
- Nutritionist: Optimizing nutrition in cases of malnutrition or eating disorders
- Subspecialists: Management of specific underlying conditions (e.g., neurosurgery for tumors)
Introduction to Delayed or Absent Puberty
Delayed puberty is defined as the absence of secondary sexual characteristics by age 13 in girls and age 14 in boys. Absent puberty, also known as pubertal failure, refers to the complete lack of pubertal development by age 18. These conditions represent significant deviations from normal pubertal timing and can have substantial physical and psychological impacts on affected individuals.
Key points to consider:
- Delayed puberty can be classified as constitutional delay of growth and puberty (CDGP) or pathological delay
- CDGP is the most common cause, especially in boys
- Early diagnosis and management are crucial to prevent complications and optimize adult outcomes
- Treatment aims to initiate pubertal development and optimize final adult height
Etiology of Delayed or Absent Puberty
1. Constitutional Delay of Growth and Puberty (CDGP)
- Most common cause (60-70% of cases)
- Normal variant of pubertal timing
- Often familial
2. Hypogonadotropic Hypogonadism (HH)
- Congenital causes:
- Kallmann syndrome
- Isolated GnRH deficiency
- CHARGE syndrome
- Prader-Willi syndrome
- Acquired causes:
- CNS tumors (e.g., craniopharyngioma, germinoma)
- Infiltrative diseases (e.g., histiocytosis, sarcoidosis)
- Head trauma
- Radiation therapy
3. Hypergonadotropic Hypogonadism
- Turner syndrome (girls)
- Klinefelter syndrome (boys)
- Gonadal dysgenesis
- Chemotherapy or radiation-induced gonadal damage
- Autoimmune ovarian failure
4. Functional Hypogonadotropic Hypogonadism
- Chronic illnesses:
- Inflammatory bowel disease
- Cystic fibrosis
- Celiac disease
- Eating disorders
- Excessive exercise
- Psychological stress
5. Endocrine Disorders
- Hypothyroidism
- Hyperprolactinemia
- Cushing's syndrome
- Growth hormone deficiency
Clinical Presentation of Delayed or Absent Puberty
1. General Signs
- Lack of secondary sexual characteristics at expected age
- Short stature or decreased growth velocity
- Delayed bone age
2. Signs in Girls
- Absence of breast development by age 13
- Lack of menarche by age 15 or within 3 years of breast development
- Primary amenorrhea
- Absent or sparse pubic and axillary hair
3. Signs in Boys
- Testicular volume <4 mL by age 14
- Lack of penile enlargement
- Absent or sparse pubic and axillary hair
- Lack of voice deepening
- Poor muscle development
4. Associated Symptoms
- Fatigue
- Decreased libido (in older adolescents)
- Emotional distress or low self-esteem
- Symptoms related to underlying conditions (e.g., anosmia in Kallmann syndrome)
Diagnosis of Delayed or Absent Puberty
1. Initial Evaluation
- Detailed history:
- Family history of pubertal timing
- Chronic illnesses
- Nutritional status and eating habits
- Exercise patterns
- Medications
- Physical examination:
- Height, weight, and BMI
- Tanner staging
- Assessment for dysmorphic features
- Neurological examination
- Growth chart evaluation
- Bone age assessment (X-ray of left hand and wrist)
2. Laboratory Tests
- Baseline hormone levels:
- LH, FSH
- Estradiol (girls) or Testosterone (boys)
- Prolactin
- TSH, free T4
- IGF-1
- GnRH stimulation test (to differentiate HH from delayed puberty)
- Karyotype analysis (especially in girls with primary amenorrhea)
- AMH and inhibin B (to assess gonadal reserve)
3. Imaging Studies
- Brain and pituitary MRI (if central cause suspected)
- Pelvic ultrasound (girls)
- Testicular ultrasound (boys)
- Bone densitometry (DEXA scan)
4. Additional Tests
- Genetic testing (for suspected genetic syndromes)
- Olfactory testing (for suspected Kallmann syndrome)
- Celiac disease screening
- Assessment for other chronic diseases based on clinical suspicion
Treatment of Delayed or Absent Puberty
1. Constitutional Delay of Growth and Puberty (CDGP)
- Reassurance and observation
- Short-term sex steroid therapy to initiate puberty:
- Boys: Low-dose testosterone
- Girls: Low-dose estrogen
2. Hypogonadotropic Hypogonadism (HH)
- Sex hormone replacement therapy:
- Boys: Testosterone replacement (various formulations)
- Girls: Estrogen replacement, followed by cyclic progestins
- Gonadotropin therapy (for fertility induction)
- Treatment of underlying causes (e.g., surgical removal of tumors)
3. Hypergonadotropic Hypogonadism
- Sex hormone replacement therapy (as in HH)
- Management of associated conditions (e.g., Turner syndrome, Klinefelter syndrome)
4. Functional Hypogonadotropic Hypogonadism
- Treatment of underlying condition (e.g., nutritional support, management of chronic diseases)
- Temporary sex hormone replacement if needed
5. Endocrine Disorders
- Specific treatment based on the underlying condition:
- Thyroid hormone replacement for hypothyroidism
- Dopamine agonists for hyperprolactinemia
- Management of Cushing's syndrome
6. Psychosocial Support
- Counseling for patients and families
- School interventions if needed
- Support groups
Prognosis and Follow-up of Delayed or Absent Puberty
1. Prognosis
- Generally good for CDGP with catch-up growth and development
- Variable for other causes, depending on underlying etiology and treatment response
- Potential long-term effects:
- Reduced final adult height
- Decreased bone mineral density
- Psychological impacts
- Fertility issues in some cases
2. Follow-up
- Regular monitoring of pubertal progression:
- Physical examination and Tanner staging
- Growth velocity assessment
- Bone age X-rays
- Periodic hormone level measurements
- Monitoring of bone health (DEXA scans)
- Adjustment of hormone replacement therapy as needed
- Fertility counseling and management in adulthood
3. Long-term Considerations
- Ongoing hormone replacement therapy for permanent hypogonadism
- Monitoring for potential complications:
- Osteoporosis
- Cardiovascular risk factors
- Metabolic syndrome
- Psychosocial support and counseling
- Genetic counseling for hereditary forms
4. Transition to Adult Care
- Education about long-term health implications
- Guidance on reproductive health and fertility options
- Continued psychological support if needed
- Coordination with adult endocrinologists for ongoing care
