The follicle is the basic functional unit of the ovary. Follicle development starts from primordial follicles and undergoes a series of changes to ultimately develop into mature follicles. Newborn girls have 700,000 to 2 million primordial follicles in both ovaries, which reduce to about 300,000 to 500,000 by age 7-9, about 40,000 at the onset of puberty, and only a few hundred by perimenopause. From menarche to menopause, under the influence of cyclic secretion of gonadotropins by the pituitary gland, one follicle matures and ovulates approximately every 28 days, with the ovaries alternating in ovulation. After ovulation, the follicle forms the corpus luteum. Throughout a woman’s life, she ovulates about 400-500 times, and the remaining follicles degenerate into atretic follicles at various ages. After menopause, the ovaries generally cease to ovulate and shrink in size.

The development and maturation of follicles/oocytes can be divided into six stages:

1. Primordial Follicle:
The primordial follicle, with a diameter of 30-60 μm, is located in the superficial cortex. It is small in size and numerous. It consists of a primary oocyte surrounded by a single layer of flat follicular cells (also called granulosa cells), encased by a thin basement membrane. The primary oocyte forms during embryonic development from oogonia and enters the first meiotic division, pausing in the prophase until ovulation.

2. Growing Follicle:
Starting from puberty, primordial follicles begin to grow and develop into growing follicles, moving towards the deeper cortex. The growing follicle stage is subdivided into primary and secondary follicles. They vary greatly in size and structure, primarily characterized by the enlargement of the oocyte and proliferation of follicular cells and surrounding connective tissue.
Primary Follicle: Develops from the primordial follicle, composed of a primary oocyte and surrounding granulosa cells. The primary oocyte enlarges, exceeding 60 μm in diameter, and the granulosa cells transform from a single layer of flat cells to multiple layers of cuboidal or columnar cells.
Secondary Follicle: When fluid-filled cavities appear between follicular cells, the growing follicle is called a secondary follicle or antral follicle. Secondary follicles have a diameter of less than 120 μm, with the granulosa cell layers increasing to 6-12 layers, forming an antrum filled with follicular fluid containing nutrients, hormones from the pituitary and ovary, and growth factors critical for follicular development.

3. Mature Follicle:
The final stage of follicle development. The mature follicle is large, with a diameter of about 20 mm, protruding from the ovarian surface. The follicular antrum is large, and the granulosa layer is thin. The oocyte resumes meiosis, completing the first meiotic division 36-48 hours before ovulation, forming a secondary oocyte and the first polar body. The secondary oocyte enters the second meiotic division, pausing at metaphase. Typically, one follicle matures and ovulates per menstrual cycle, taking approximately 85 days from the late primary follicle stage to mature ovulation.

4. Ovulation:
Ovulation is the process where the mature follicle ruptures, releasing the secondary oocyte, corona radiata, zona pellucida, and follicular fluid from the ovary. It occurs around the 14th day of the menstrual cycle. Before ovulation, the primary oocyte becomes a secondary oocyte, and a surge of LH from the pituitary triggers a series of changes in the follicle. The follicular fluid increases, the follicle wall, tunica albuginea, and surface epithelium thin, and local ischemia forms a stigma. During ovulation, the stigma ruptures due to the action of enzymes and prostaglandins, releasing the oocyte and surrounding cells into the peritoneal cavity and then into the fallopian tube. If not fertilized within 24 hours, the secondary oocyte degenerates. If fertilized, it completes the second meiotic division, forming a mature ovum and the second polar body. The chromosomal number is halved from diploid (46, XX) to haploid (23, X). The ovarian surface heals the rupture site in about 2-4 days.

5. Corpus Luteum Formation and Regression:
After ovulation, the remaining granulosa cells and theca cells collapse into the antrum, forming the corpus luteum, which is yellow in color due to its rich vascular content. The granulosa cells become large lutein cells, secreting progesterone, while the theca cells become smaller lutein cells, secreting estrogen. If the oocyte is not fertilized, the corpus luteum lasts about two weeks (menstrual corpus luteum), then regresses into the corpus albicans. If fertilized, the corpus luteum enlarges under the influence of hCG from the placenta, reaching 4-5 cm (pregnancy corpus luteum), and remains for six months before regressing into the corpus albicans. Progesterone production is taken over by the placenta in later stages. Lutein cells also secrete relaxin to relax the uterine smooth muscle during pregnancy.

6. Follicular Atresia:
Atresia can occur at any follicular stage, lacking consistent morphological changes. Most follicles do not reach maturity, instead undergoing atresia at various stages. Atresia is controlled by apoptosis, maintaining a balance of mature follicles for reproductive needs while preventing excessive ovulation. The process varies with the size of the oocyte: in primordial and primary follicles, granulosa cell nuclei condense, and the oocyte becomes irregular and eventually autolyzes. In secondary and mature follicles, the oocyte degenerates, and the zona pellucida shrinks. Atresia involves apoptosis of granulosa cells and the oocyte, a normal ovarian function.