Fetal & Neonatal Endocrinology

Forfar & Arneil 7th Edition · Fetal hormone ontogeny · Placental hormones · Maternal disease/drugs · Neonatal endocrine presentations: hypoglycemia, micropenis, ambiguous genitalia, prolonged jaundice, salt wasting, hypothermia, SGA, undescended testes, screening
📌 Key principles: Fetal hormone secretion develops in a specific ontogenic sequence. Neonatal endocrine emergencies include salt-wasting CAH (hyponatremia, hyperkalemia, shock), congenital hypothyroidism (prolonged jaundice, hypotonia), and hypoglycemia (hyperinsulinism, GHD, adrenal insufficiency). Newborn screening detects CHT and CAH in many countries.

📖 Fetal & Neonatal Endocrinology: Core Concepts

👶 Fetal endocrine ontogeny
Hypothalamus develops by 8-10 weeks. Pituitary corticotrophs secrete ACTH by 8 weeks; GH by 10 weeks. Thyroid follicles appear at 10 weeks, T4 by 12 weeks. Fetal adrenal cortex (fetal zone) produces DHEAS, important for placental oestrogen synthesis.
🤰 Placental hormones
hCG (maintains corpus luteum), hPL (maternal metabolic adaptation), oestrogen (from fetal DHEAS), progesterone (maintains pregnancy). Maternal hormones do not cross placenta significantly (except thyroid hormones and IgG).
⚡ Neonatal hypoglycemia causes
Hyperinsulinism (IDM, Beckwith-Wiedemann, nesidioblastosis), GH deficiency, adrenal insufficiency, inborn errors (fatty acid oxidation, glycogen storage). SGA and prematurity also at risk.
🩺 Neonatal endocrine emergencies
Salt-wasting CAH (hyponatremia, hyperkalemia, shock, vomiting). Congenital hypothyroidism (prolonged jaundice, hypotonia, macroglossia, umbilical hernia). Hypoglycemia with seizures requires urgent glucose.
🔬 Neonatal screening
Congenital hypothyroidism (TSH), CAH (17-OHP), CF, PKU, MCADD, sickle cell. Early treatment prevents intellectual disability and death. Universal newborn hearing screening also routine.
📊 Key neonatal presentations: Micropenis (stretched penile length <2.5cm in term) → hypogonadotropic hypogonadism (Kallmann, Prader-Willi) or GH deficiency. Ambiguous genitalia → CAH (46,XX virilized) or 46,XY undervirilized (androgen insensitivity, 5-alpha reductase, gonadal dysgenesis).

🔍 Structured approach to neonatal endocrine presentations

1
Hypoglycemia in neonate – Blood glucose <2.6 mmol/L. Assess: gestational age, birth weight, SGA, maternal diabetes, drug history. Determine glucose requirement (mg/kg/min). >8 mg/kg/min suggests hyperinsulinism. Check insulin, C-peptide, cortisol, GH, ketones, lactate, ammonia, acylcarnitine profile.
2
Micropenis (stretched penile length <2.5 cm in term) – Exclude hypospadias. Evaluate: LH, FSH, testosterone (basal and after hCG stimulation). Karyotype. Consider hypogonadotropic hypogonadism (Kallmann, Prader-Willi, septo-optic dysplasia) or GH deficiency.
3
Ambiguous genitalia – Emergency: assign sex after expert evaluation, exclude salt-wasting CAH (electrolytes, 17-OHP). Karyotype (rapid FISH), pelvic ultrasound (presence of uterus), genitogram. 46,XX virilized: CAH most common. 46,XY undervirilized: androgen insensitivity, 5-alpha reductase, gonadal dysgenesis.
4
Prolonged jaundice (>14 days term, >21 days preterm) – Check conjugated/unconjugated bilirubin. Unconjugated: breast milk jaundice, Crigler-Najjar, Gilbert, hypothyroidism (check TSH/fT4). Conjugated: biliary atresia, neonatal hepatitis, metabolic.
5
Salt wasting (vomiting, hyponatremia, hyperkalemia, shock) – Suspect congenital adrenal hyperplasia (21-hydroxylase deficiency). Emergency: hydrocortisone IV, 0.9% saline bolus, fludrocortisone. Confirm with 17-OHP, electrolytes, renin.
6
Hypothermia, poor feeding, large fontanelle, hoarse cry – Congenital hypothyroidism. Check TSH, fT4. Newborn screening TSH elevated. Start levothyroxine immediately.
📌 Clinical pearl: In a sick neonate with vomiting, hyponatremia, and hyperkalemia, always consider salt-wasting CAH. Do not delay hydrocortisone while awaiting confirmation. Misdiagnosis as sepsis or pyloric stenosis can be fatal.

📋 Stepwise management of neonatal endocrine disorders

1
Congenital hypothyroidism (CHT) – Confirm venous TSH and fT4. Start levothyroxine 10-15 mcg/kg/day (full dose). Monitor TSH, fT4 every 1-2 months in first year. Goal: TSH 0.5-5 mIU/L, fT4 in upper half. Most thyroid dysgenesis; rarely transient.
2
Salt-wasting CAH (21-hydroxylase deficiency) – Resuscitation: IV 0.9% saline 20 ml/kg bolus, then maintenance with 5% dextrose/0.9% saline. Hydrocortisone 50-100 mg/m² IV, then 50 mg/m²/day divided q6h. Fludrocortisone 0.05-0.2 mg/day orally. Correct hyperkalemia (calcium, insulin/glucose if severe).
3
Neonatal hypoglycemia – hyperinsulinism – Glucose infusion >8 mg/kg/min required. Diazoxide (5-15 mg/kg/day) if hyperinsulinism confirmed. Somatostatin (octreotide) for refractory. Consider subtotal pancreatectomy if medical failure.
4
Micropenis – evaluation & management – hCG stimulation test (2000 IU IM weekly x 3) to assess testosterone response. Testosterone enanthate 25 mg IM monthly for 3 months if hypogonadism. Genetic counseling.
5
Ambiguous genitalia – gender assignment – Multidisciplinary team (endocrinology, surgery, genetics, psychology). Avoid gonadectomy in 46,XY undervirilized without uterus unless malignancy risk (intra-abdominal testes after puberty). CAH females: corrective surgery deferred until 6-12 months.
6
SGA (small for gestational age) – endocrine screening – Monitor growth. If no catch-up by age 2 years, evaluate for GH deficiency, hypothyroidism. GH therapy approved for SGA without catch-up (height <-2.5 SDS).
7
Undescended testes – Confirm bilateral palpation. If bilateral non-palpable, consider congenital adrenal hyperplasia (in 46,XY virilized?) or hypogonadotropic hypogonadism. Karyotype, hCG stimulation test, MRI for intra-abdominal testes.
⚠️ Newborn screening (UK): PKU, CHT, CF, sickle cell disease, MCADD. Some regions screen for CAH, galactosemia, biotinidase deficiency, other metabolic disorders.

🧠 Reflex prompts: fetal & neonatal endocrinology

👶 A 2-week-old with vomiting, poor feeding, hyponatremia (Na 118), hyperkalemia (K 7.1), hypotension. First step?
Salt-wasting CAH. IV hydrocortisone, 0.9% saline bolus, then maintenance fluids with glucose. Check 17-OHP urgently.
🩺 A 6-week-old with prolonged jaundice (unconjugated), hypotonia, umbilical hernia, macroglossia. Diagnosis?
Congenital hypothyroidism. Confirm TSH, fT4. Start levothyroxine immediately. Newborn screening may have missed if not done.
🍼 A term infant with birth weight 4.5 kg, macrosomia, hypoglycemia (glucose 1.2 mmol/L) at 2 hours. Mother not diabetic. Next step?
Hyperinsulinism (possible Beckwith-Wiedemann or focal adenoma). Check insulin, C-peptide. Glucose requirement >8 mg/kg/min. Diazoxide if confirmed.
🧬 A newborn with ambiguous genitalia, palpable gonads bilaterally, no uterus on ultrasound. Karyotype?
46,XY (male pseudohermaphroditism). Workup: 17-OHP (normal in CAH?), androgen insensitivity (high testosterone, normal LH), 5-alpha reductase deficiency (low DHT).
📏 A term male newborn has stretched penile length 1.8 cm. Testes descended bilaterally. Next investigation?
Micropenis. Check LH, FSH, testosterone (basal and post-hCG). Karyotype. MRI brain for hypogonadotropic hypogonadism (Kallmann, septo-optic dysplasia).
🔬 A 3-day-old screening TSH is 120 mIU/L. Confirmatory venous TSH 150, fT4 <2 pmol/L. Management?
Start levothyroxine 10-15 mcg/kg/day immediately. Thyroid ultrasound to identify ectopic/hypoplastic gland. Monitor growth, development.
👶 A preterm SGA infant has persistent hypoglycemia requiring 12 mg/kg/min glucose. Insulin elevated. Most likely?
Hyperinsulinemic hypoglycemia. Consider diazoxide trial. Genetic testing for ABCC8/KCNJ11 mutations (KATP channel).
⚡ A neonate with bilateral non-palpable testes, clitoromegaly, labioscrotal fusion. Karyotype 46,XY. Diagnosis?
Disorder of sexual development (46,XY DSD). Exclude CAH (17-OHP normal?). Check hCG stimulation test, anti-Müllerian hormone, pelvic MRI for uterus/fallopian tubes.
🩺 Maternal Graves disease – newborn has tachycardia, irritability, poor weight gain. What antibody is responsible?
Maternal TRAb (thyroid stimulating immunoglobulin) crosses placenta, causes neonatal Graves hyperthyroidism. Usually transient (weeks to months). Carbimazole or propranolol if severe.
🧪 What hormone is measured in newborn screening for congenital adrenal hyperplasia?
17-hydroxyprogesterone (17-OHP) on dried blood spot. Elevated in 21-hydroxylase deficiency (classic and simple virilizing forms).