Follicular Development

Follicular development is the process by which an ovarian follicle (the oocyte with its surrounding supporting cells) progresses through a defined sequence of structural stages. It proceeds in parallel with oogenesis and is functionally inseparable from it.

The primary oocyte does not develop in isolation. It develops only within the structural and hormonal environment of its follicle at each successive stage.

A primordial follicle is the earliest and most basic follicular structure. It consists of a primary oocyte, arrested at diplotene of prophase I, surrounded by a single layer of flattened, squamous follicular cells and enclosed by a basement membrane.

Primordial follicles are formed during late fetal life. They make up a woman's total, fixed, non-renewable follicular reserve, the pool from which every follicle that will ever develop in her reproductive lifespan is drawn.

No new primordial follicles are formed after this fetal establishment. The pool only ever declines from its peak. Some follicles are recruited into further development. Far more commonly, follicles undergo atresia, which is programmed degeneration without completing development.

A primordial follicle that begins development is first recognised as a primary follicle once its surrounding follicular cells change from a flattened, squamous shape to a cuboidal shape. The oocyte itself begins to enlarge.

A distinct, thick, acellular glycoprotein layer, the zona pellucida, begins to form at this stage immediately around the oocyte. It lies between the oocyte's own plasma membrane and the surrounding follicular cells.

As development continues, the single layer of cuboidal follicular cells proliferates into multiple layers. These cells are now termed granulosa cells.

A primary follicle with multiple granulosa cell layers is sometimes distinguished as a late primary, or preantral multilaminar, follicle. The defining feature throughout remains the absence of any fluid-filled cavity within the follicle at this stage.

A secondary follicle is characterised by further proliferation of the granulosa cell layers. A distinct layer of stromal cells appears immediately external to the granulosa cells and is organised into the theca folliculi.

The theca folliculi differentiates into an inner, hormonally active theca interna and an outer, more fibrous theca externa.

The theca interna develops the capacity to respond to luteinising hormone and to synthesise androgens. These are transferred to the adjacent granulosa cells and converted into oestrogens.

From this stage onward, this establishes the fundamental two-cell, two-gonadotrophin cooperative hormonal relationship between theca and granulosa cells. It underlies ovarian oestrogen production throughout the remainder of follicular development.

An antral follicle, sometimes termed a tertiary follicle, is defined by a fluid-filled cavity, the antrum, within the granulosa cell layer. Small fluid-filled spaces initially appear between granulosa cells as follicular fluid, rich in hormones and other secreted factors, accumulates. They coalesce to form the antrum.

As the antrum enlarges, the granulosa cells become organised into distinct regional populations:

• Mural granulosa cells line the outer wall of the follicle.
• The cumulus oophorus is a specialised cluster of granulosa cells immediately surrounding the oocyte. It remains attached to the oocyte and travels with it at ovulation.
• The corona radiata is the innermost, closely adherent layer of cells directly encasing the oocyte.

The mature, or Graafian, follicle is the final stage of follicular development before ovulation. It has a single large, dominant antral cavity and a fully developed cumulus-oocyte complex.

The oocyte is a secondary oocyte, following completion of meiosis I shortly before ovulation, and is poised for release.

Under normal physiological circumstances, a single dominant follicle is selected from the larger cohort of antral follicles recruited in a menstrual cycle. This follicle proceeds to full maturity and ovulation.

The remaining follicles of the recruited cohort undergo atresia rather than reaching full maturity. This selection ensures that ordinarily only a single oocyte is released per cycle in the normal ovulatory human cycle.

Throughout every stage of follicular development, the oocyte and its surrounding follicular or granulosa cells are closely and bidirectionally dependent. The follicular cells are not merely passive packaging around an independently developing oocyte.

The surrounding cells:

• Supply nutrients and regulatory signals to the oocyte via gap junctions, which persist across the zona pellucida throughout most of follicular development.
• Actively support the oocyte's growth and its progression through meiotic arrest and eventual resumption.
• Are in turn influenced by factors secreted by the oocyte, which regulate granulosa cell proliferation and differentiation.

This reciprocal relationship is why an oocyte cannot complete normal development in isolation from its follicular environment.

The functional developmental unit throughout this process is therefore the whole structure, the oocyte together with its surrounding somatic cells, not the oocyte alone.