What are the causes and treatment options for delayed growth in females?

Delayed Growth in Females: Causes and Treatment

Definition and Initial Assessment

Delayed puberty in females is defined as the absence of breast development (Tanner stage 2) by age 13 years or failure to progress in pubertal stage for ≥12 months, or primary amenorrhea by age 16 years. 1, 2

Key Clinical Parameters to Evaluate

• Growth velocity and height percentiles relative to genetic target height using mid-parental height calculations 1
• Bone age assessment via left wrist radiography to determine growth potential and differentiate constitutional delay from pathological causes 1, 2
• Tanner staging to document degree of pubertal development 3
• Menstrual history including presence or absence of menarche and cycle regularity 2, 4

Diagnostic Framework: Three Main Categories

1. Constitutional Delay of Growth and Puberty (CDGP)

CDGP is the most common cause, accounting for 30% of delayed puberty in females (compared to 60% in males). 5 This represents a benign developmental variant where puberty occurs later than average but progresses normally once initiated. 2, 6

Key features:

• Family history of late puberty 3, 2
• Delayed bone age consistent with height age 1, 2
• Normal growth velocity for bone age 6
• Low-normal FSH/LH levels 4

2. Hypergonadotropic Hypogonadism (Ovarian Failure)

This category indicates primary ovarian dysfunction with elevated FSH/LH levels. 4

Causes include:

• Turner syndrome and other chromosomal abnormalities - most common pathological cause 2, 5
• Premature ovarian insufficiency (POI) - defined as amenorrhea ≥4 months with two elevated FSH levels in menopausal range before age 40 1
• Gonadal dysgenesis 5, 4
• Chemotherapy/radiation exposure - particularly alkylating agents and pelvic radiation 1
• Autoimmune oophoritis 5

Diagnostic approach:

• Karyotype analysis mandatory 2, 5
• Two FSH measurements in menopausal range (separated by at least 4 weeks) 1
• Pelvic ultrasound to assess ovarian morphology 3

3. Hypogonadotropic Hypogonadism (Central Causes)

This category shows low or low-normal FSH/LH with poorly developed secondary sexual characteristics, indicating hypothalamic-pituitary dysfunction. 4

Subdivided into:

A. Permanent hypogonadotropic hypogonadism:

• Kallmann syndrome (with anosmia) 2, 5
• Idiopathic hypogonadotropic hypogonadism 2, 5
• Pituitary tumors (prolactinomas, craniopharyngiomas) 7, 5
• Congenital pituitary deficiencies 5

B. Transient/functional hypogonadotropic hypogonadism:

• Chronic systemic illness (asthma, inflammatory bowel disease, celiac disease) 6, 5
• Nutritional deficiency and eating disorders 1, 2
• Excessive exercise/athletic training 2, 5
• Hypothyroidism 1, 8
• Hyperprolactinemia 8, 7

Structured Diagnostic Algorithm

Step 1: Initial Laboratory Evaluation

Obtain the following baseline tests:

• FSH and LH levels - single measurement to categorize hypogonadism type 3, 2, 4
• Estradiol level - to assess ovarian function 3, 9
• Prolactin level - essential to rule out hyperprolactinemia 8, 7
• TSH and free T3 - hypothyroidism can cause delayed puberty even with normal prolactin 1, 8
• IGF-1 level - to assess growth hormone status and rule out mixed hormone deficiency 1, 7
• Complete blood count, comprehensive metabolic panel - to screen for chronic disease 2

Step 2: Imaging Studies

Based on initial findings:

• Bone age X-ray (left wrist) - mandatory in all cases to assess skeletal maturation 1, 3, 2
• Pelvic ultrasound - if hypergonadotropic hypogonadism suspected or to rule out ovarian pathology 3, 4
• Brain MRI with pituitary protocol - indicated if:
  • Hypogonadotropic hypogonadism confirmed 3, 2
  • Elevated prolactin levels 8
  • Neurological symptoms present 3
  • Very young age at presentation (<6 years) 3

Step 3: Genetic Testing

Karyotype analysis indicated when:

• Hypergonadotropic hypogonadism identified 2, 5
• Short stature with delayed puberty 2
• Dysmorphic features present 2

Treatment Approach by Etiology

Constitutional Delay of Growth and Puberty

Treatment goals: optimize final height, bone health, and psychosocial well-being. 2, 6

Management options:

1. Observation with reassurance - appropriate if patient/family comfortable waiting 2, 6
2. Low-dose estrogen therapy - when psychosocial concerns significant 9, 2, 5
   • Start with conjugated estrogens 0.3 mg daily or equivalent 9
   • Gradually increase dose over 2-3 years to mimic normal puberty 5
   • Add cyclic progestin after 12-24 months of estrogen or when breakthrough bleeding occurs 9, 5

Critical pitfall: Large repeated doses of estrogen can accelerate epiphyseal closure, resulting in compromised final height if initiated before completion of physiologic puberty. 9 Therefore, use lowest effective doses and monitor bone age every 6-12 months. 9

Hypergonadotropic Hypogonadism (Ovarian Failure)

Lifelong hormone replacement therapy required. 5, 4

Treatment protocol:

• Estrogen therapy initiated at diagnosis to induce pubertal development 9, 5
• Start with low doses (conjugated estrogens 0.3 mg or equivalent) 9
• Gradually escalate over 2-3 years to adult replacement doses 5
• Add progestin after 12-24 months of estrogen to protect endometrium 9, 5
• Calcium and vitamin D supplementation essential for bone health 10
• Fertility counseling - discuss egg donation options early 2, 5

For cancer survivors with POI risk:

• Surveillance with menstrual history monitoring 1
• FSH measurement if amenorrhea ≥4 months develops 1
• Early intervention to optimize bone health 1, 10

Permanent Hypogonadotropic Hypogonadism

Two treatment approaches available:

1. Traditional hormone replacement (standard approach):

• Estrogen therapy as described above 9, 5
• Progesterone added cyclically 9, 5

2. Physiological induction therapy (preferred for fertility preservation):

• hCG monotherapy or hCG + FSH combination 5
• Pulsatile GnRH infusion 5
• These protocols recommended to increase long-term fertility success, though no clear consensus exists on optimal regimens 5

For prolactinomas:

• Dopamine agonists (cabergoline or bromocriptine) first-line treatment 7
• Monitor prolactin levels to assess treatment efficacy 8
• May discontinue after 6 months of normal prolactin with periodic monitoring 8

Functional/Transient Hypogonadotropic Hypogonadism

Address underlying cause as primary treatment:

Nutritional deficiency:

• Optimize caloric intake to achieve appropriate weight for height 1, 2
• Consider nasogastric or gastrostomy feeding if severe malnutrition 1
• Puberty often resumes spontaneously with nutritional rehabilitation 2, 6

Hypothyroidism:

• Thyroid hormone replacement 1, 8
• Women on thyroid therapy may require higher doses when estrogen added 9

Hyperprolactinemia:

• Treat underlying cause (discontinue offending medications if possible) 8
• Dopamine agonists if prolactinoma or idiopathic hyperprolactinemia 8, 7

Chronic disease:

• Optimize disease control 6, 5
• Correct metabolic acidosis (target bicarbonate ≥22 mEq/L) in renal disease 1
• Ensure adequate sodium and water supplementation in salt-wasting conditions 1

Long-term Monitoring and Complications

Bone Health Concerns

Delayed puberty compromises peak bone mass acquisition, increasing osteoporosis risk. 6, 10 This represents a paradigm shift from viewing delayed puberty as purely benign. 6

Monitoring recommendations:

• Baseline DEXA scan at diagnosis if age >16 years 10
• Repeat DEXA every 1-2 years during treatment 10
• Ensure adequate calcium (1200-1500 mg daily) and vitamin D (600-1000 IU daily) 10

Height Outcomes

Final adult height may be compromised in some individuals with delayed puberty history. 10 Monitor growth velocity and bone age progression closely during treatment. 1, 9

Psychosocial Impact

Delayed puberty negatively affects psychosocial functioning and educational achievement. 10 Early intervention warranted when significant distress present, even in constitutional delay. 2, 6

Metabolic and Cardiovascular Risk

Adults with delayed puberty history carry higher risk for metabolic and cardiovascular disorders. 10 Long-term follow-up should include screening for these conditions. 10

Protective Effects

Delayed puberty appears protective for breast and endometrial cancer in women. 10 This should be discussed when counseling patients about their condition. 10

Critical Pitfalls to Avoid

1. Failing to differentiate CDGP from permanent hypogonadotropic hypogonadism - remains challenging but critical for appropriate management 2, 5
2. Initiating broad-spectrum testing in healthy adolescents - often low clinical value; target testing based on history and exam 2
3. Using excessive estrogen doses - accelerates epiphyseal closure and compromises final height 9
4. Neglecting bone health monitoring - delayed puberty has lasting effects on bone density 6, 10
5. Missing prolactinomas - check prolactin in all cases of delayed puberty with amenorrhea 8, 7
6. Overlooking fertility preservation - discuss early, especially in hypergonadotropic hypogonadism 2, 5
7. Dismissing psychosocial impact - can persist even after normal development achieved 6, 10