Abnormal Puberty & Reproductive Disorders

Forfar & Arneil 7th Edition · Precocious puberty (central/peripheral) · Delayed puberty · Amenorrhea · Noonan syndrome · Klinefelter syndrome · Gynecomastia · Undescended testes
📌 Key principles: Precocious puberty: <8y girls, <9y boys. Central (GnRH-dependent) vs peripheral (GnRH-independent). Delayed puberty: girls >13y no breast, boys >14y testicular volume <4ml. Noonan (short, webbed neck, pulmonic stenosis, normal karyotype). Klinefelter (47,XXY, tall, small testes, gynecomastia).

📖 Abnormal Puberty & Reproductive Disorders: Core Concepts

⏩ Central precocious puberty (CPP)
GnRH-dependent, pulsatile LH. Aetiology: idiopathic (most girls), hypothalamic hamartoma, CNS tumours, trauma, irradiation. Treated with GnRH agonists.
⚡ Peripheral precocious puberty (PPP)
GnRH-independent. Causes: McCune-Albright (girls), testotoxicosis (boys, activating LH receptor), CAH, adrenal/ovarian/testicular tumours.
⏸️ Delayed puberty
Girls >13y no breast, boys >14y testicular volume <4ml. Causes: constitutional delay (most common), hypogonadotropic hypogonadism (Kallmann, pituitary), hypergonadotropic (Turner, Klinefelter).
🩺 Noonan syndrome
Autosomal dominant (PTPN11 mutation), short stature, webbed neck, pulmonic stenosis, hypertelorism, cryptorchidism, normal karyotype (46,XX/XY). GH therapy approved.
🧬 Klinefelter syndrome (47,XXY)
Tall stature, small firm testes, gynecomastia, azoospermia, learning difficulties. Testosterone replacement after puberty. Increased risk of breast cancer, osteoporosis.
📊 Key diagnoses: Gynecomastia: common in pubertal boys (Tanner 2-4), usually benign. Undescended testes (cryptorchidism): >90% descend by 6 months; if not, refer for surgery (orchiopexy) by 12-18 months.

🔍 Clinical approach to abnormal puberty & reproductive disorders

1
Precocious puberty – initial evaluation – Confirm pubertal signs. Bone age advanced? Growth acceleration? Girls: breast development <8y, boys: testicular enlargement <9y. Distinguish benign variants (thelarche, adrenarche).
2
Differentiate central vs peripheral – GnRH agonist test (leuprolide). Stimulated LH >5 IU/L → central. Flat response → peripheral. Basal LH/FSH may help but stimulation is gold standard.
3
Imaging for CPP – MRI brain (hypothalamic hamartoma, tumour, hydrocephalus). Pelvic ultrasound in girls (ovarian size, cysts).
4
Delayed puberty – initial workup – Tanner staging, bone age, LH/FSH, testosterone/oestradiol. Karyotype (Turner, Klinefelter). MRI pituitary/hypothalamus if low gonadotropins. Smell test (Kallmann).
5
Noonan syndrome diagnosis – Clinical features (short stature, webbed neck, pectus, pulmonic stenosis, hypertelorism, low-set ears, cryptorchidism). Genetic testing PTPN11, KRAS, SOS1, RAF1.
6
Klinefelter syndrome – Karyotype 47,XXY. Hypergonadotropic hypogonadism (high FSH, low testosterone after puberty). Testosterone replacement for hypogonadism.
7
Gynecomastia – evaluation – Differentiate from pseudogynecomastia (fat). Check pubertal stage. Exclude pathological causes (Klinefelter, testicular tumour, liver disease, hyperthyroidism, drugs).
📌 Clinical pearl: In a girl with breast development <8y but normal growth velocity and bone age, consider premature thelarche (benign). If bone age advanced and growth acceleration, do GnRH stimulation test.

📋 Stepwise management of abnormal puberty & reproductive disorders

1
Central precocious puberty (CPP) – GnRH agonist (leuprolide acetate) monthly IM. Halts pubertal progression, improves adult height. Monitor bone age, growth velocity, LH suppression.
2
Peripheral precocious puberty (PPP) – Treat underlying cause: McCune-Albright: aromatase inhibitors (letrozole, anastrozole), tamoxifen. Testotoxicosis: ketoconazole, spironolactone, bicalutamide. CAH: glucocorticoids.
3
Delayed puberty – constitutional delay – Reassure. If psychosocial distress: low-dose testosterone (boys 50-100 mg IM monthly x 4-6 months) or oestrogen (girls 0.3-0.6 mcg/kg/day). Monitor bone age.
4
Hypogonadotropic hypogonadism – Sex hormone replacement (testosterone enanthate or transdermal; oestrogen + progesterone). Pulsatile GnRH or gonadotropins for fertility.
5
Turner syndrome – management – GH therapy for short stature. Oestrogen replacement at age 11-12y. Cardiac monitoring (bicuspid aortic valve, coarctation, aortic dissection risk).
6
Klinefelter syndrome – management – Testosterone replacement (after 12y) to induce virilisation, improve bone density, energy. Speech therapy, educational support.
7
Undescended testes (cryptorchidism) – If not descended by 6 months, refer to paediatric surgeon. Orchiopexy before 12-18 months to preserve fertility, reduce malignancy risk. Bilateral non-palpable: karyotype, hCG stimulation.
⚠️ Red flags in gynecomastia: Sudden onset, painful, unilateral, associated with testicular mass, very large breasts, prepubertal onset → investigate (testicular ultrasound, LH, testosterone, hCG).

🧠 Reflex prompts: abnormal puberty & reproductive disorders

👧 A 7-year-old girl with breast development (Tanner B3), pubic hair PH2, growth acceleration, bone age 9 years. Next step?
GnRH agonist test. Stimulated LH >5 IU/L confirms central precocious puberty. MRI brain to exclude hamartoma/tumour.
👦 A 6-year-old boy with penile enlargement, pubic hair, testicular volume 8 ml, advanced bone age. Most likely?
Central precocious puberty (boys). Idiopathic or CNS lesion. GnRH agonist test. MRI brain.
👧 A 4-year-old girl with vaginal bleeding, breast development, café-au-lait spots, fibrous dysplasia. Diagnosis?
McCune-Albright syndrome (peripheral precocious puberty). Oestrogen elevated, LH suppressed. Aromatase inhibitors.
🧬 A 14-year-old boy with delayed puberty (testes 2 ml), short stature, webbed neck, low posterior hairline, pulmonic stenosis. Karyotype?
Noonan syndrome (46,XY). PTPN11 mutation common. GH therapy may be used.
🩺 A 16-year-old boy with tall stature, small firm testes, gynecomastia, learning difficulties. Diagnosis?
Klinefelter syndrome (47,XXY). Hypergonadotropic hypogonadism. Testosterone replacement.
📏 A 15-year-old boy with delayed puberty, anosmia, low LH/FSH, normal MRI. Diagnosis?
Kallmann syndrome (normosmic variant or anosmic). Pulsatile GnRH or gonadotropins for fertility.
⚧ A 14-year-old girl with primary amenorrhea, normal breast development, absent uterus, 46,XY karyotype. Diagnosis?
Complete androgen insensitivity syndrome (CAIS). Testes, no uterus, high testosterone. Gonadectomy after puberty.
🩸 A 15-year-old girl with primary amenorrhea, short stature, webbed neck, high FSH. Diagnosis?
Turner syndrome (45,XO). Oestrogen replacement, GH for height.
🍼 A newborn with bilateral non-palpable testes, micropenis, hypospadias. Karyotype 46,XY. Next step?
hCG stimulation test to assess testicular function. May need testosterone replacement and surgical exploration.
🧪 A 14-year-old boy with unilateral painful gynecomastia, testicular mass. Testicular ultrasound shows solid mass. Next step?
Suspicious for Leydig cell tumour or Sertoli cell tumour. Beta-hCG, AFP, testosterone. Surgical referral.