Type 1 Endometrial Cancer Etiology
Type 1 endometrial cancer is caused by excess estrogen exposure—either endogenous or exogenous—that stimulates endometrial cell proliferation unopposed by progesterone. 1
Primary Mechanism: Hyperestrogenism
The fundamental pathophysiology centers on estrogen-driven endometrial hyperplasia that progresses to malignant transformation when progesterone is insufficient to counterbalance proliferative signals. 1 This hormonal imbalance creates continuous endometrial stimulation, leading to the characteristic well-differentiated to moderately differentiated endometrioid adenocarcinomas that define Type 1 disease. 1
Endogenous Estrogen Sources
Obesity is the dominant risk factor for Type 1 endometrial cancer, as adipose tissue converts androgens to estrogen through aromatization, creating a hyperestrogenic state. 1 Additional endogenous sources include:
- Early menarche and late menopause—both extend the lifetime duration of estrogen exposure 1
- Chronic anovulation (as seen in PCOS)—results in continuous estrogen without cyclic progesterone opposition, increasing risk nearly threefold (OR 2.79-2.89) 2
- Nulliparity—eliminates the protective effect of pregnancy-related progesterone exposure 1
Exogenous Estrogen Sources
- Unopposed estrogen hormone replacement therapy (prescribed without progesterone) dramatically increases risk 10-30 fold with 5+ years of use 2
- Tamoxifen use—acts as an estrogen agonist in the endometrium despite being an antagonist in breast tissue 1
Associated Metabolic Conditions
Metabolic syndrome components cluster with Type 1 endometrial cancer, reflecting the interconnected nature of hormonal and metabolic dysregulation. 1 Patients frequently present with:
- Diabetes mellitus—associated with both hyperinsulinemia and insulin resistance, which may independently promote endometrial proliferation 1
- Hyperlipidemia 1
- Anovulatory uterine bleeding 1
The metabolic syndrome itself has been identified as an independent risk factor beyond its individual components. 1
Genetic Predisposition (Minority of Cases)
While most Type 1 cancers are sporadic, approximately 3-5% arise from hereditary syndromes: 1
- Lynch syndrome—germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM) confer 40-60% lifetime endometrial cancer risk 1
- Cowden syndrome—PTEN, SDHB, SDHD, and KLLN gene variations 1
Clinical Implications
Type 1 cancers comprise 70% of all endometrial cancers and carry a favorable prognosis, typically presenting at early stage with endometrioid histology. 1 At least 90% express moderate to high levels of estrogen receptor, confirming their hormone-dependent nature. 1 The precursor lesion is endometrial intraepithelial neoplasia (distinct from the endometrial intraepithelial carcinoma seen in Type 2 disease). 1
Common Pitfall to Avoid
Do not confuse the estrogen-dependent Type 1 pathway with Type 2 endometrial cancers (serous, clear cell, carcinosarcoma), which are estrogen-independent, occur in nonobese women without metabolic disorders, lack association with endometrial hyperplasia, and carry significantly worse prognosis. 1