What is the mechanism by which human chorionic gonadotropin (hCG) causes nausea?

Why hCG Causes Nausea

Human chorionic gonadotropin (hCG) causes nausea primarily through two mechanisms: elevated hCG levels directly trigger nausea and vomiting, and progesterone (which is maintained by hCG) delays gastric emptying, causing food to sit in the stomach longer and exacerbating nausea. 1

Primary Mechanisms

Direct Hormonal Effects

• Elevated hCG levels are the primary driver of nausea and vomiting in pregnancy, with symptoms peaking at 10-12 weeks gestation when hCG concentrations are highest 1, 2
• The severity of nausea correlates with hCG concentration—conditions with abnormally high hCG (twin pregnancies, molar pregnancies, hyperemesis gravidarum) consistently show more severe nausea and vomiting 2, 3
• In hyperemesis gravidarum, approximately one-third to two-thirds of patients have biochemical evidence of increased thyroid function due to hCG's weak thyroid-stimulating activity, which may contribute to nausea 2

Progesterone-Mediated Gastric Effects

• Progesterone, whose production is maintained by hCG, inhibits gastrointestinal motility and causes delayed gastric emptying, which directly contributes to nausea by causing food to remain in the stomach longer 1, 4
• This delayed gastric emptying means large meals sit in the stomach longer, leading to gastric overdistension and worsening nausea 1

Clinical Evidence Supporting the hCG-Nausea Connection

Dose-Response Relationship

• Normal pregnancy shows TSH suppression at 10-12 weeks when hCG peaks, indicating significant hormonal activity 2
• Twin pregnancies with higher hCG levels demonstrate more frequent TSH suppression and more severe nausea 2
• Trophoblastic tumors secreting very large amounts of hCG (>200 IU/mL) commonly cause both hyperthyroidism and severe nausea 2

Molecular Variants

• Certain molecular variants of hCG with increased biological potency (basic molecules with reduced sialic acid content, truncated molecules, or nicked beta-subunit molecules) may explain why some women develop severe hyperemesis gravidarum while others with similar hCG levels do not 2
• Patients with hyperemesis gravidarum likely secrete a variant of hCG with increased thyroid-stimulating and potentially increased nauseogenic activity 2

Important Clinical Caveats

Not All High hCG Causes Severe Symptoms

• While hCG is clearly implicated, the relationship is not perfectly linear—individual susceptibility varies, suggesting additional factors (genetic, metabolic, immunological) modulate the response to hCG 3
• The exact mechanism by which hCG triggers the nausea reflex in the central nervous system remains incompletely understood 5, 3

Multiple Hormones Involved

• Estrogen levels also rise during early pregnancy and contribute to nausea, working synergistically with hCG 1, 3
• Other hormones including leptin, placental growth hormone, prolactin, and thyroid hormones have been implicated but their roles are less well-established 3

Timing Confirms Causation

• The temporal relationship is compelling: nausea typically begins around 4-6 weeks gestation as hCG rises, peaks at 10-12 weeks when hCG is highest, and resolves by 16-20 weeks in 80% of cases as hCG levels decline 1, 6