trophoblast

**Origin and timeline** - Trophoblast cells arise from the outer cell mass of the blastocyst (days 4-5, after the morula stage). The inner cell mass (embryoblast) forms the embryo proper. - Implantation begins around day 6-7 (week 1). By the end of week 2 the trophoblast has differentiated into two layers.

**Two layers** 1. **Cytotrophoblast** (inner layer): single cells with distinct borders. It is mitotically active and acts as the stem-cell layer. It gives rise to syncytiotrophoblast and later extravillous trophoblast. 2. **Syncytiotrophoblast** (outer layer): multinucleated, with no cell borders and no mitoses. It is invasive and erodes the endometrial stroma and maternal vessels, which establishes the lacunar and uteroplacental circulation. It **secretes hCG**, which maintains the corpus luteum (progesterone production) until about weeks 8-10, when the placenta takes over. hCG is detectable in maternal blood about 8 days after fertilization (urine about 2 weeks) and is the basis of pregnancy tests. The syncytiotrophoblast also makes hPL (human placental lactogen), progesterone, and estrogen later in gestation. It forms the placental barrier together with the fetal capillary endothelium.

**Derivatives** - Chorion (trophoblast plus extraembryonic mesoderm) -> chorionic villi -> fetal part of the placenta. - The maternal part of the placenta is the decidua basalis, derived from endometrium. - Extravillous trophoblast invades and remodels the spiral arteries into low-resistance, high-capacity vessels.

**Clinical correlations (high-yield)** - **Ectopic pregnancy**: implantation outside the uterine cavity, most often in the ampulla of the fallopian tube. Risk factors are PID, prior ectopic pregnancy, tubal surgery, and IUD. Presents with abdominal pain, vaginal bleeding, and a positive hCG. Treat with methotrexate if stable and unruptured, or surgery if ruptured or unstable. - **Placenta accreta spectrum** (accreta, increta, percreta): there is abnormally deep trophoblast invasion because of a defective decidua basalis (for example, over a prior C-section scar or with placenta previa). Presents with severe postpartum hemorrhage when the placenta fails to separate. - **Preeclampsia**: there is inadequate remodeling of the spiral arteries by extravillous trophoblast. This causes placental ischemia, release of anti-angiogenic factors (sFlt-1), endothelial dysfunction, hypertension, and proteinuria. - **Gestational trophoblastic disease**: - *Complete mole*: 46,XX (paternal origin, an empty egg fertilized by a sperm that duplicates). There is no fetal tissue, diffuse villous swelling ("honeycomb" or "cluster of grapes" on ultrasound, "snowstorm" appearance), and markedly elevated hCG. It carries a higher risk of choriocarcinoma, and hCG can cause hyperthyroidism, theca-lutein cysts, and hyperemesis. - *Partial mole*: triploid (69,XXY) with fetal parts. It has a lower risk of malignancy and a more modest hCG elevation. - *Choriocarcinoma*: malignant trophoblastic tumor with sheets of cytotrophoblast and syncytiotrophoblast and **no chorionic villi**. It spreads hematogenously, especially to lung (cannonball metastases). It has very high hCG and is highly chemosensitive (methotrexate or actinomycin D). - **Placental site trophoblastic tumor**: derives from intermediate trophoblast. It makes hPL, has low hCG, and responds poorly to chemotherapy. - **Pregnancy tests and hCG**: hCG is made by syncytiotrophoblast. It is structurally similar to LH, FSH, and TSH (shared alpha subunit, with a unique beta subunit), which explains hyperthyroidism in molar pregnancy.

**Memory aids** - "Syncytio = Secretes hCG" and "Cyto = Cells that divide (stem)". - Trophoblast = "nourishing" (trophe = nutrition) layer that feeds and anchors the embryo.