Growth Regulation, Obesity & Pubertal Endocrinology

Forfar & Arneil 7th Edition · GH-IGF-1 axis · Short/tall child · Obesity & thinness · Adrenarche · Gonadarche · Pubertal initiation · Body composition & metabolic signals
📌 Key principles: GH secreted in pulses, stimulates IGF-1 production. Height velocity is best marker of growth. Obesity → insulin resistance, early puberty in girls, delayed in boys. Adrenarche (DHEA) separate from gonadarche (LH/FSH). Leptin signals metabolic readiness for puberty.

📖 Growth regulation, obesity & pubertal endocrinology

🧬 GH-IGF-1 axis
Hypothalamic GHRH stimulates pituitary GH (pulsatile). GH acts on liver to produce IGF-1 (somatomedin). IGF-1 mediates growth, feeds back to suppress GH. Somatostatin inhibits GH.
📏 Short/slowly growing child – causes
Familial short stature, constitutional delay, GHD, hypothyroidism, Turner, SGA, chronic disease, psychosocial, skeletal dysplasia. Height velocity <4 cm/year pathological.
🍔 Obesity in children
BMI >95th centile. Most common: exogenous. Endocrine causes: hypothyroidism, Cushing, pseudohypoparathyroidism, hypothalamic obesity. Leptin resistance common.
🔬 Adrenarche vs gonadarche
Adrenarche: adrenal DHEA (ages 6-8) → pubic/axillary hair, apocrine odour. Gonadarche: GnRH pulses → LH/FSH → gonadal sex steroids → breast/testicular development.
⚖️ Metabolic signals for puberty
Leptin (from adipose tissue) permissive for GnRH pulses. Critical body fat threshold. Underweight delays puberty; obesity (girls) advances onset.
📊 Key investigations: IGF-1, IGFBP-3, bone age, GH stimulation tests, TSH/fT4, karyotype (Turner), coeliac screen, inflammatory markers, MRI pituitary (if GHD or hypopituitarism).

🔍 Clinical approach to growth disorders, obesity & pubertal variations

1
Short stature – initial evaluation – Accurate height, weight, calculate height velocity, mid-parental height, bone age. Rule out chronic disease (coeliac, IBD, renal, cardiac). Thyroid function, IGF-1, karyotype in girls.
2
Investigation of GH axis – Low IGF-1 with delayed bone age suggests GHD. GH stimulation tests (clonidine, glucagon, arginine) – peak GH <7 mcg/L indicates deficiency. MRI pituitary for structural abnormalities.
3
Obesity – endocrine causes – Hypothyroidism (TSH, fT4), Cushing syndrome (UFC, dexamethasone suppression test), pseudohypoparathyroidism (calcium, PTH), hypothalamic obesity (MRI). Genetic syndromes: Prader-Willi, Bardet-Biedl, Alström, leptin deficiency.
4
Thinness / underweight – Exclude chronic disease, malabsorption (coeliac, CF), hyperthyroidism, diabetes, eating disorders. Low IGF-1 may reflect malnutrition rather than GHD.
5
Pubertal maturation – normal physiology – Adrenarche (DHEA) independent of gonadarche. Onset of puberty requires GnRH pulse generator activation (inhibited in childhood by GABA, neurokinin B). Leptin threshold necessary.
6
Variations of puberty – Premature thelarche (isolated breast), premature adrenarche (pubic hair only), both benign. Delayed puberty: constitutional vs hypogonadotropic vs hypergonadotropic.
📌 Clinical pearl: A child with height <0.4th centile and height velocity <4 cm/year (after age 4) needs investigation regardless of bone age. IGF-1 can be normal in GHD; GH stimulation tests are required for diagnosis.

📋 Stepwise management of growth, obesity & pubertal disorders

1
GH deficiency – treatment – Recombinant GH 25-50 mcg/kg/day subcutaneous. Monitor height velocity, IGF-1, bone age annually. Treat underlying cause (e.g., craniopharyngioma surgery).
2
Idiopathic short stature (ISS) – GH therapy approved if height <-2.25 SDS, growth velocity low, no other cause. Modest height gain (~4-7 cm). Cost-effectiveness debated.
3
Obesity – lifestyle intervention – Dietary modification, increased physical activity, behavioral therapy. Pharmacotherapy (orlistat) rarely in adolescents. Bariatric surgery in severe adolescent obesity with comorbidities.
4
Hypothalamic obesity (e.g., craniopharyngioma) – Difficult to treat; combination of diet, exercise, sometimes metformin, GLP-1 agonists, or bariatric surgery.
5
Delayed puberty – treatment – Constitutional delay: reassurance. Low-dose testosterone (boys 50-100 mg IM monthly) or oestrogen (girls 0.3-0.6 mcg/kg/day) if psychosocial distress. Hypogonadotropic hypogonadism requires long-term sex hormone replacement.
6
Precocious puberty (central) – GnRH agonist (leuprolide) monthly IM. Peripheral precocious puberty: treat cause (CAH with glucocorticoids, McCune-Albright with aromatase inhibitors/fulvestrant).
7
Thinness – investigation & management – Rule out hyperthyroidism (TSH, fT4), diabetes (glucose), malabsorption (coeliac antibodies, fecal elastase). Nutritional support, treat underlying disorder.
⚠️ Key concepts in pubertal initiation: Gonadarche = reactivation of GnRH pulse generator (inhibited during childhood by GABAergic tone). Adrenarche = adrenal androgen secretion (DHEA, DHEAS) independent of gonads. Leptin required for GnRH secretion; low leptin delays puberty.

🧠 Reflex prompts: growth, obesity & pubertal endocrinology

📏 A 7-year-old boy height <3rd centile, growth velocity 3.5 cm/year, bone age 4 years, IGF-1 low. Next step?
GH stimulation test. Low IGF-1 + delayed bone age + poor growth velocity suggests GHD. MRI pituitary to exclude structural lesion.
🍔 A 12-year-old girl with BMI 32 kg/m² (98th centile), acanthosis nigricans, normal thyroid function. Most likely diagnosis?
Exogenous obesity with insulin resistance. Screen for diabetes (HbA1c, OGTT). Treat with lifestyle modification; metformin if insulin resistance severe.
🧪 A 5-year-old with obesity, short stature, round face, striae, hypertension. First test?
Overnight dexamethasone suppression test to screen for Cushing syndrome. If abnormal, proceed to 24h UFC, MRI pituitary.
⚡ A 13-year-old boy with delayed puberty, low LH/FSH, normal smell. Diagnosis?
Hypogonadotropic hypogonadism (normosmic). Differentiate from constitutional delay with GnRH stimulation test (flat response → HH).
🦋 A 9-year-old girl with obesity, short stature, constipation, dry skin, TSH 8.5 (normal <5), fT4 11 (normal 12-22). Next step?
Subclinical hypothyroidism. Check anti-TPO antibodies. May not require treatment if asymptomatic; treat with levothyroxine if symptomatic or goiter.
📈 What is the role of leptin in puberty onset?
Leptin (from adipocytes) acts as a permissive signal for GnRH secretion. Critical body fat mass threshold required. Leptin deficiency causes delayed puberty; replacement restores.
👧 A 7-year-old girl with breast development (B2), pubic hair PH2, growth velocity 7 cm/year, bone age 8 years. Next step?
GnRH agonist test. If stimulated LH >5 IU/L → central precocious puberty. If flat → peripheral (adrenal or ovarian source).
🔬 A 4-year-old with pubic hair (PH2), normal growth, bone age 4.5 years. Diagnosis?
Premature adrenarche (benign isolated pubic hair). No treatment, but monitor for signs of true precocious puberty.
🧠 A 10-year-old with rapid weight gain, hyperphagia, hypotonia, small hands/feet, hypogonadism. Genetic syndrome?
Prader-Willi syndrome (deletion 15q11.2). GH therapy approved (improves body composition, growth, strength).
🩺 A 14-year-old girl with primary amenorrhea, delayed puberty, low IGF-1, normal LH/FSH, normal TSH. Diagnosis?
Functional hypogonadotropic hypogonadism due to underweight (eating disorder, excessive exercise). Restore weight → menses.