Folliculogenesis

Although the process is similar in many animals, this article will deal exclusively with human folliculogenesis.

Folliculogenesis starts in prenatal development with the establishment of a large pool of primordial follicles. Each primordial follicle consists of an oocyte surrounded by a shell of somatic granulosa cells. The early shell is of flattened pre-granulosa cells also known as follicular cells.

It continues under hormonal influence at puberty with the primordial follicles progressively changing to preovulatory follicles containing egg cells that are capable of being fertilised on release. This stage takes place in the menstrual cycle as the follicular phase of the ovarian cycle, and takes around two and a half months. Primordial follicles firstly develop into primary follicles which may be recruited for further development in the cycle.

Unlike male spermatogenesis, which can last indefinitely, folliculogenesis ends when the remaining follicles in the ovaries are incapable of responding to the hormonal cues that previously recruited some follicles to mature. This depletion in follicle supply signals the beginning of menopause.

Stages

Folliculogenesis is continuous, meaning that at any time the ovary contains follicles in many stages of development. The majority of follicles die (follicular atresia) and never complete development. A few develop fully into a tertiary follicle containing a mature oocyte capable of being fertilised, which is released by rupture of the follicle in the process of ovulation.

The growing follicle passes through the following distinct stages that are defined by certain structural characteristics:

In addition, follicles that have formed an antrum are called antral follicles that may progress to mature or Graafian follicles. Definitions differ in where this shift occurs in the staging given above, with some stating that it occurs when entering the secondary stage, and others stating that it occurs when entering the tertiary stage.

Until the preovulatory stage, the follicle contains a primary oocyte that is arrested in prophase of meiosis I. During the late preovulatory stage, the oocyte continues meiosis and becomes a secondary oocyte, arrested in metaphase II.

Primordial

At 18–22 weeks post-conception, the cortex of the ovary contains its peak number of follicles (about 4 to 5 million in the average case, but individual peak populations range from 6 to 7 million). These primordial follicles contain immature oocytes surrounded by flat, squamous granulosa cells (support cells) that are segregated from the oocyte's environment by the basal lamina. They are quiescent, showing little to no biological activity. Because primordial follicles can be dormant for up to 50 years in humans, the length of the ovarian cycle does not include this time.

During the maturation of the primary oocyte an oocyte maturation inhibitor (OMI) is created by follicular cells. OMI is a small peptide, an inhibitory factor believed to be the reason why the oocyte remains for so long in the immature dictyate state of meiosis.

The supply of follicles decreases slightly before birth, and to 500,000 by puberty for the average case (populations at puberty range from 25,000 to 1.5 million). By virtue of the "inefficient" nature of folliculogenesis (discussed later), only 400–500 of these follicles will ever reach the preovulatory stage. At menopause, only 1,000 follicles remain. It seems likely that early menopause occurs for women with low populations at birth, and late menopause occurs for women with high populations at birth, but there is as yet no clinical evidence for this.

The process by which primordial cells 'wake up' is known as initial recruitment. Research has shown that initial recruitment is mediated by the counterbalance of various stimulatory and inhibitory hormones and locally produced growth factors.

Primary

During ovarian follicle activation, the follicular cells of the primordial follicles change from squamous to cuboidal granulosa cells, marking the beginning of the primary follicle. The oocyte genome is activated and genes become transcribed. Rudimentary paracrine signaling pathways that are vital for communication between the granulosa cells and oocyte are formed. Both the oocyte and the follicle grow dramatically, increasing to almost 0.1 mm in diameter.

Primary follicles develop receptors to follicle stimulating hormone (FSH) at this time, but they are gonadotropin-independent until the antral stage. Research has shown, however, that the presence of FSH accelerates follicle growth in vitro.

A glycoprotein polymer capsule called the zona pellucida forms around the oocyte, separating it from the surrounding granulosa cells. The zona pellucida, which remains with the oocyte after ovulation, contains enzymes that catalyze with sperm to allow penetration.

Secondary

Stroma-like theca cells are recruited by oocyte-secreted signals. They surround the follicle's outermost layer, the basal lamina, and undergo cytodifferentiation to become the theca externa and theca interna. An intricate network of capillary vessels forms between these two thecal layers and begins to circulate blood to and from the follicle.

The late-term secondary follicle is marked histologically and structurally by a fully grown oocyte surrounded by a zona pellucida, approximately nine layers of granulosa cells, a basal lamina, a theca interna, a capillary net, and a theca externa. The development of the antrum also starts taking place in secondary follicle stage.

Antrum formation

The formation of a fluid-filled cavity in the secondary follicle called the follicular antrum designates the follicle as an antral follicle, in contrast to a so-called preantral follicle that still lacks an antrum.

Follicular fluid fills the antrum that surrounds the oocyte in the follicle. The appearance of follicular fluid during follicular maturation is the first sign that a follicle has reached the next stage of maturation. The fluid is rich in hyaluronic acid, and is used in a modified intracytoplasmic sperm injection (ICSI) called physiological ICSI (PICSI), semi-viscous and yellow in colour. Its components come mainly from granulosa cells.

Early tertiary

In the tertiary follicle, the basic structure of the mature follicle has formed and no novel cells are detectable. Granulosa and theca cells continue to undergo mitosis concomitant with an increase in antrum volume. Tertiary follicles can attain a tremendous size that is hampered only by the availability of FSH, which it is now dependent on.

Under action of an oocyte-secreted morphogenic gradient, the granulosa cells of the tertiary follicle undergo differentiation into four distinct subtypes: corona radiata, surrounding the zona pellucida; membrana, interior to the basal lamina; periantral, adjacent to the antrum and cumulus oophorus, which connects the membrana and corona radiata granulosa cells together. Each type of cell behaves differently in response to FSH.

Theca interna cells express receptors for luteinizing hormone (LH). LH induces the production of androgens by the theca cells, most notably androstendione, which are aromatized by granulosa cells to produce estrogens, primarily estradiol. Consequently, estrogen levels begin to rise.

Late tertiary and preovulatory (the follicular phase of the menstrual cycle)

At this point, the majority of the group of follicles that started growth have died. This process of follicle death is known as atresia, and it is characterized by radical apoptosis of all constituent cells and the oocyte. Although it is not known what causes atresia, the presence of high concentrations of FSH has been shown to prevent it.

A rise in pituitary FSH caused by the disintegration of the corpus luteum at the conclusion of a menstrual cycle precipitates the recruitment of five to seven class 5 follicles to participate in the next cycle. These follicles enter the end of the prior menstrual cycle and transition into the follicular phase of the next one. The selected follicles, called antral follicles, compete with each other for growth-inducing FSH.

The pattern of this emergence of a cohort of five to seven antral follicles is debated. There are theories of continuous recruitment of antral follicles, theories of a single recruitment episode at the end of the luteal phase, and more recently there has been evidence for a recruitment model marked by 2 - 3 waves of follicle recruitment and development during the menstrual cycle (only one of which is actually an ovulatory wave).

In response to the rise of FSH, the antral follicles begin to secrete estrogen and inhibin, which have a negative feedback effect on FSH. Follicles that have fewer FSH-receptors will not be able to develop further; they will show retardation of their growth rate and become atretic. Eventually, only one follicle will be viable. This remaining follicle, called the dominant follicle, will grow quickly and dramatically—up to 20 mm in diameter—to become the preovulatory follicle.

The follicular phase of the menstrual cycle is the time between selection of a tertiary follicle and its subsequent growth into a preovulatory follicle. The actual time for development of a follicle varies.

The growth of the dominant follicle during the follicular phase is about 1.5 mm per day (±0.1 mm), both in natural cycles and for any dominant follicle developing while taking combined oral contraceptive pill. Performing controlled ovarian hyperstimulation leads to a greater recruitment of follicles, growing at about 1.6 mm per day.