hCG

**Structure:** Heterodimeric glycoprotein. The α subunit is shared with LH, FSH, and TSH; the β subunit is unique and confers specificity (hence β-hCG is used in assays). hCG binds the LH/hCG receptor (Gs-coupled GPCR → ↑cAMP).

**Source and physiology:** - Produced by syncytiotrophoblast after implantation (~6-9 days after fertilization). - Rescues the corpus luteum → continued progesterone secretion until the placenta takes over (luteal-placental shift, ~8-10 weeks). - Levels roughly double every 48-72 hours in early normal pregnancy, peak at ~8-10 weeks (about 100,000 mIU/mL), then fall to a plateau for the rest of pregnancy. - Stimulates fetal Leydig cells to make testosterone (male sexual differentiation in the first trimester). - Structural similarity to TSH (shared α subunit) → at very high levels, hCG weakly stimulates the TSH receptor → gestational transient thyrotoxicosis and hyperemesis gravidarum. - Associated with nausea/vomiting of pregnancy (levels peak at the same time).

**Clinical uses:** - Diagnosis of pregnancy: urine (qualitative, point-of-care) and serum (quantitative) tests. - Ectopic pregnancy: hCG rises abnormally slowly (<53% rise in 48 hrs) or plateaus. Discriminatory zone: when hCG is above ~1,500-3,500 mIU/mL, an intrauterine gestational sac should be visible on transvaginal ultrasound; if none is seen → suspect ectopic. - Threatened or incomplete abortion or failed pregnancy: hCG falls or fails to rise appropriately. - Quad screen (15-22 weeks): ↑hCG and ↑inhibin A with ↓AFP and ↓unconjugated estriol = Down syndrome (trisomy 21). Trisomy 18 (Edwards) = all four markers ↓. First trimester screen: ↑free β-hCG and ↓PAPP-A in Down syndrome. - Neoplasm tumor marker: - **Hydatidiform mole**: markedly ↑hCG (greater than expected for gestational age), "snowstorm" appearance on ultrasound, uterine size greater than dates, theca lutein cysts, hyperemesis, early preeclampsia, hyperthyroidism. Complete mole is 46,XX (all paternal, empty egg), with no fetal parts and a "cluster of grapes" appearance. Partial mole is triploid (69,XXX/XXY/XYY), with fetal parts present. - **Choriocarcinoma**: malignant trophoblastic tumor with very high hCG, hematogenous spread to lung ("cannonball" mets), no chorionic villi, and a good response to methotrexate. It may follow a mole, abortion, or normal pregnancy. It can also occur as a testicular germ cell tumor, which may cause gynecomastia. - Testicular germ cell tumors (seminoma with syncytiotrophoblastic giant cells, embryonal carcinoma, choriocarcinoma) can ↑hCG. - Mole/choriocarcinoma follow-up: serial hCG monitoring after evacuation; effective contraception is needed during surveillance to avoid confusion with a new pregnancy. - Exogenous hCG: used for ovulation induction (acts like an LH surge in IVF) and for cryptorchidism or hypogonadotropic hypogonadism in males.

**Pearls / pitfalls:** - False-positive: heterophilic antibodies, hCG-secreting tumors, pituitary hCG (perimenopausal), and recent miscarriage or abortion. - "Hook effect" (very high hCG saturates the assay antibodies → false-negative qualitative test; dilute the sample), seen in molar pregnancy or choriocarcinoma. - Low hCG for gestational age: ectopic pregnancy, blighted ovum, impending abortion, wrong dates. - High hCG for gestational age: multiple gestation, molar pregnancy, Down syndrome, erythroblastosis fetalis/hydrops. - Because hCG is stable and rises early, it is used in nearly every pregnancy workup question; always check hCG before imaging or medications in a woman of reproductive age with abdominal pain, and in ectopic cases consider methotrexate when hemodynamically stable.