What is the role of Luteinizing Hormone (LH) receptors on granulosa cells, given that Follicle-Stimulating Hormone (FSH) is the primary stimulator of these cells?

LH Receptors on Granulosa Cells: Developmental Expression and Functional Significance

LH receptors appear on granulosa cells during follicular maturation to enable the transition from FSH-dependent growth to LH-dependent ovulation and luteinization—this is a critical developmental switch that occurs progressively as follicles mature from small antral stages through preovulatory stages.

Sequential Receptor Expression During Follicular Development

The presence of LH receptors on granulosa cells represents a carefully orchestrated developmental program rather than a contradiction:

• Granulosa cells in small antral follicles (3-10 mm) already express LH receptors at approximately 10% of maximum levels, demonstrating that LH signaling begins much earlier in follicular development than previously recognized 1

• LH receptor expression increases progressively as follicles mature, reaching maximal levels in preovulatory follicles just before ovulation 1

• FSH initially induces LH receptor expression in granulosa cells, establishing the foundation for subsequent LH responsiveness 2, 3

The Two-Gonadotropin, Two-Cell Model Extended

While FSH remains the primary driver of early follicular development, LH receptors serve distinct and essential functions:

• LH maintains and amplifies its own receptor expression through positive autoregulation once FSH has initiated receptor induction—this homologous upregulation involves new protein synthesis and increases receptor numbers without changing binding affinity 2

• LH receptor expression correlates significantly with aromatase (CYP19a1) gene expression and follicular fluid estradiol and progesterone concentrations, indicating LH participates in steroidogenesis throughout the follicular phase 1

• FSH receptor expression progressively declines as follicular diameter increases, while LH receptor expression increases, representing a developmental handoff of gonadotropin dominance 1

Critical Functions of LH Receptors on Granulosa Cells

Pre-Ovulatory Functions

• LH triggers rapid structural reorganization of the follicle, stimulating LH receptor-expressing mural granulosa cells to extend inward and intercalate between other cells within 30 minutes of the LH surge 4

• LH induces immediate early gene expression in granulosa cells within 1 hour, upregulating 57 transcripts including transcription factors (Nr4a1, Nr4a2, Egr1, Egr2) and EGF-like ligands (Areg, Ereg, Epgn) that initiate ovulation and luteinization cascades 5

Luteinization Functions

• LH receptors are prerequisite for corpus luteum formation, as ovarian follicles cannot ovulate or luteinize without functional LH receptor signaling 2, 3

Regulatory Complexity

The expression and function of LH receptors on granulosa cells is modulated by multiple factors:

• FSH, LH, and prolactin all maintain LH receptor mRNA levels in FSH-primed granulosa cells 3

• Growth factors provide negative regulation: basic fibroblast growth factor and epidermal growth factor suppress FSH-induced LH receptor mRNA in a dose-dependent manner 3

• GnRH suppresses LH receptor mRNA levels through specific GnRH-binding sites on granulosa cells, providing an additional layer of regulation 3

Clinical Relevance

Understanding LH receptor expression on granulosa cells has direct clinical implications:

• Granulosa cell tumors express steroid hormone receptors and may respond to hormonal therapies including GnRH agonists and aromatase inhibitors 6

• Inhibin B serves as the primary tumor marker for granulosa cell tumors (89% sensitivity, 100% specificity), reflecting the hormone-producing capacity of these cells 7