beta-hCG

**Structure:** hCG is a heterodimeric glycoprotein with an α-subunit and a β-subunit. The α-subunit is identical to that of LH, FSH, and TSH. The β-subunit is unique, which gives hormone specificity, so pregnancy tests detect the β-subunit. hCG's β-subunit is structurally similar to LH's, and hCG binds the LH receptor.

**Physiology:** - Produced by syncytiotrophoblast (not cytotrophoblast) after implantation. - Rescues the corpus luteum, so it keeps secreting progesterone until the placenta takes over (luteal-placental shift, ~8-10 weeks). - Peaks at ~8-10 weeks, then declines to a plateau. - Stimulates fetal testicular Leydig cells to make testosterone (male sexual differentiation). - High levels can weakly stimulate the TSH receptor (α-subunit homology), causing transient gestational hyperthyroidism and contributing to hyperemesis gravidarum.

**Clinical use:** - Serum quantitative β-hCG is detectable ~8-11 days after conception. Urine qualitative tests are positive at about 1 week after conception or a missed period. - Normal early pregnancy: levels rise ~doubling every 48-72 hours (a minimum rise of ~35-53% in 48 h is acceptable at lower starting levels). - Discriminatory zone: ~1,500-3,500 mIU/mL. If β-hCG is above this and the transvaginal ultrasound shows no intrauterine gestational sac, suspect ectopic pregnancy or failed pregnancy. - Abnormally slow rise or plateau suggests ectopic pregnancy or impending miscarriage. A fall of at least 21-35% over 48 h is typical after spontaneous or medical abortion. Monitor until undetectable.

**Elevated β-hCG (higher than expected):** - Multiple gestation - Molar pregnancy (complete mole: very high levels, "snowstorm" appearance, no fetal parts, 46,XX paternal origin; partial mole: triploid, 69,XXY, fetal parts present) - Down syndrome (trisomy 21) on the quad screen (↑ hCG, ↑ inhibin A, ↓ AFP, ↓ estriol) - Gestational trophoblastic neoplasia (choriocarcinoma) - Hydrops fetalis, erythroblastosis fetalis

**Decreased β-hCG:** - Edwards syndrome (trisomy 18): ↓ hCG, ↓ AFP, ↓ estriol, normal or ↓ inhibin A - Ectopic pregnancy (lower than expected for dates) - Impending or missed abortion

**Non-pregnancy sources/tumor marker:** - Choriocarcinoma (gestational or germ cell): very high β-hCG, with hematogenous spread to lung ("cannonball" metastases). It is chemosensitive (methotrexate or actinomycin D). - Testicular germ cell tumors: seminoma (can have mildly ↑ hCG from syncytiotrophoblastic giant cells), choriocarcinoma, and embryonal carcinoma. Choriocarcinoma can cause gynecomastia and hyperthyroidism in men. - Hydatidiform mole can cause theca lutein cysts (bilateral ovarian enlargement from very high hCG), early preeclampsia (before 20 weeks), hyperthyroidism, and hyperemesis. - Pituitary hCG is a rare benign cause of low-level elevation in perimenopausal women (the "phantom hCG" differential also includes heterophile antibodies, which cause false-positive serum tests but negative urine tests).

**Pearls:** - Always check β-hCG in a reproductive-age woman with abdominal pain, abnormal bleeding, or before imaging or medications. - Ectopic pregnancy triad: amenorrhea, abdominal pain, and vaginal bleeding. Risk factors include PID, prior ectopic, tubal surgery, and IUD. Management is methotrexate if stable and β-hCG is low (generally <5,000), with no fetal cardiac activity and no rupture. Surgery is needed if unstable or ruptured. - After molar evacuation, follow β-hCG weekly until undetectable, then monthly (persistent elevation suggests persistent GTN, which is treated with methotrexate). - Post-abortion or post-delivery hCG can stay detectable for weeks. - Hook effect: very high hCG levels can cause a false-negative urine test (such as in a molar pregnancy), which is fixed by diluting the sample.