What are the functions of estrogen and progesterone on the endometrium?

Functions of Estrogen and Progesterone on the Endometrium

Estrogen drives endometrial proliferation and growth, while progesterone opposes this proliferative effect by inducing differentiation, secretory transformation, and acting as the primary tumor suppressor in the endometrium. 1

Estrogen Functions

Proliferative Effects:

• Estrogen stimulates endometrial proliferation during the follicular/proliferative phase of the menstrual cycle, causing the mucosa to thicken and grow 2
• Acts through specific nuclear estrogen receptors (ERα and ERβ) located in both epithelial and stromal cells of the endometrium 2, 3
• Stimulates synthesis of its own receptors (upregulation) and induces synthesis of progesterone receptors, which is essential for subsequent progesterone activity 2

Receptor Dynamics:

• ERα primarily mediates proliferative effects and is the dominant receptor in non-pregnant endometrium 1
• ERβ serves a protective role by restraining ERα-mediated proliferative responses and is dynamically expressed throughout the menstrual cycle 3
• The balance between ERα and ERβ determines the net estrogenic effect on endometrial tissue 3

Clinical Implications:

• Unopposed estrogen (without progesterone) leads to continuous endometrial proliferation, hyperplasia, and increased risk of endometrial cancer 4, 5
• The risk of endometrial cancer with unopposed estrogen is 2- to 12-fold greater than in non-users, with greatest risk (15- to 24-fold) associated with 5-10 years of use 4

Progesterone Functions

Anti-Proliferative and Differentiation Effects:

• Progesterone transforms proliferative endometrium into secretory endometrium, arresting glandular proliferation 6, 2
• Inhibits synthesis of estrogen receptors, thereby opposing estrogen's proliferative effects 2
• Induces cellular differentiation and secretory changes in glandular epithelium 6, 5

Tumor Suppressor Role:

• Progesterone functions as the ultimate endometrial tumor suppressor - women who ovulate regularly and produce progesterone almost never develop endometrial cancer 7
• Inhibits estrogen-driven growth and prevents progression from hyperplasia to carcinoma 7, 8
• Progestin therapy can reverse endometrial hyperplasia in approximately 75% of cases 1

Structural Changes:

• Induces stromal decidualization (transformation of stromal cells) 5
• Promotes development of spiral arterioles in the endometrium 5
• Creates the secretory endometrium necessary for embryo implantation during the "window of implantation" 1

Coordinated Hormonal Regulation

Cyclic Changes:

• The endometrium undergoes cyclic growth, differentiation, desquamation, and regeneration driven by ovarian estrogen and progesterone 1
• During the proliferative phase, estrogen dominates; during the secretory phase, progesterone dominates while estrogen levels remain present 2

Endometrial Protection:

• Adding progestin to estrogen therapy for 10-13 days per cycle provides maximal endometrial maturation and eliminates hyperplastic changes 6
• Combined estrogen-progestin therapy reduces the risk of endometrial hyperplasia compared to estrogen alone 6, 4
• For women with intact uteri receiving hormone replacement, progestin must be added to estrogen to protect the endometrium 1, 4

Clinical Pitfalls

Common Errors to Avoid:

• Never prescribe estrogen alone in women with an intact uterus - this creates unopposed estrogen stimulation and significantly increases endometrial cancer risk 4, 5
• Insufficient duration of progestin exposure (less than 10 days per cycle) may not adequately protect the endometrium from hyperplasia 6
• In fertility-preserving treatment for early endometrial cancer, high-dose progestins (medroxyprogesterone acetate 400-600 mg/day or megestrol acetate 160-320 mg/day) are required, not physiologic doses 1