Inbiology,folliculogenesis is the maturation of theovarian follicle, a densely packed shell ofsomatic cells that contains an immatureoocyte. Folliculogenesis describes the progression of a number of smallprimordial follicles into largepreovulatory follicles that occurs in part during themenstrual cycle.
Contrary to malespermatogenesis, which can last indefinitely, folliculogenesis ends when the remaining follicles in theovaries are incapable of responding to the hormonal cues that previously recruited some follicles to mature. This depletion in follicle supply signals the beginning ofmenopause.Each cycle of folliculogenesis, for a follicle, lasts around 2 months and a half.
The primary role of the follicle isoocyte support. From the whole pool of follicles a woman is born with, only 0.1% of them will rise ovulation, whereas 99.9% will break down (in a process calledfollicular atresia). From birth, theovaries of the human female contain many immature,primordial follicles. These follicles each contain a similarly immatureprimary oocyte. Atpuberty, clutches of follicles begin folliculogenesis, entering a growth pattern that ends in ovulation (the process where the oocyte leaves the follicle) or in atresia (death of the follicle's granulosa cells).[citation needed]
During follicular development, primordial follicles undergo a series of critical changes in character, both histologically and hormonally. First they change into primary follicles and later into secondary follicles. The follicles then transition totertiary, or antral, follicles. At this stage in development, they become dependent on hormones, particularly FSH which causes a substantial increase in their growth rate.The late tertiary or pre-ovulatory follicle ruptures and discharges the oocyte (that has become asecondary oocyte), ending folliculogenesis.
Follicle 'selection' is the process by which a single 'dominant' follicle is chosen from the recruited cohort or wave for preferential growth. It has generally been documented to occur once in the early- to mid- follicular phase of the menstrual cycle, leading to ovulation.[1]
Folliculogenesis is continuous, meaning that at any time the ovary contains follicles in many stages of development. The majority of follicles die and never complete development. A few develop fully to produce a secondary oocyte which is released by rupture of the follicle in a process calledovulation.
The growing follicle passes through the following distinct stages that are defined by certain structural characteristics:
In a larger perspective, the whole folliculogenesis, from primordial to preovulatory follicle, belongs to the stage ofootidogenesis ofoogenesis.
| Stage | Description | Size |
|---|---|---|
| Primordial | Dormant, small, only one layer of flatgranulosa cells | Primordial follicles are about 0.03–0.05 mm in diameter. |
| Primary | Mitotic cells,cuboidal granulosa cells | Almost 0.1 mm in diameter |
| Secondary | Presence oftheca cells, multiple layers of granulosa cells | The follicle is now 0.2 mm in diameter |
| Early tertiary | The early tertiary follicle is arbitrarily divided into five classes. Class 1 follicles are 0.2 mm in diameter, class 2 about 0.4 mm, class 3 about 0.9 mm, class 4 about 2 mm, and class 5 about 5 mm. | |
| Late tertiary | Fully formedantrum, no further cytodifferentiation, no novel progress | Class 6 follicles are about 10 mm in diameter, class 7 about 16 mm, and class 8 about 20 mm. It is common for non-dominant follicles to grow beyond class 5, but rarely is there more than one class 8 follicle. |
| Preovulatory | Building growth in estrogen concentration, all other folliclesatretic or dead |
In addition, follicles that have formed anantrum are calledantral follicles or Graafian follicles. Definitions differ in where this shift occurs in the staging given above, with some stating that it occurs when entering thesecondary stage,[2] and others stating that it occurs when entering thetertiary stage.[3]
Until the preovulatory stage, the follicle contains a primary oocyte that is arrested in prophase ofmeiosis I. During the late preovulatory stage, the oocyte continues meiosis and becomes a secondary oocyte, arrested inmetaphase II.
At 18–22 weeks post-conception, the cortex of the femaleovary (foetal female 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).[4] Theseprimordial follicles contain immature oocytes surrounded by flat, squamousgranulosa cells (support cells) that are segregated from the oocyte's environment by the basal lamina. They are quiescent, showing little to nobiological 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.
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).[4] By virtue of the "inefficient" nature of folliculogenesis (discussed later), only 400–500 of these follicles will ever reach the preovulatory stage. Atmenopause, 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.[4]
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.[5]
Duringovarian follicle activation, the granulosa cells of the primordial follicles change from a flat to a cuboidal structure, marking the beginning of theprimary follicle. The oocyte genome is activated and genes becometranscribed. Rudimentaryparacrine signaling pathways that are vital for communication between the follicle and oocyte are formed. Both the oocyte and the follicle grow dramatically, increasing to almost 0.1 mm in diameter.[citation needed]
Primary follicles develop receptors tofollicle 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 growthin vitro.
A glycoprotein polymer capsule called thezona 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.
Stroma-like theca cells are recruited by oocyte-secreted signals. They surround the follicle's outermost layer, thebasal lamina, and undergo cytodifferentiation to become thetheca externa andtheca 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
The formation of a fluid-filled cavity adjacent to the oocyte called theantrum designates the follicle as anantral follicle, in contrast to a so-calledpreantral follicle that still lacks an antrum. An antral follicle is also called aGraafian follicle.
Definitions differ as to which stage this shift occurs in, with some designating follicles in thesecondary stage asantral,[2] and others designating them aspreantral.[3]
In thetertiary 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 andcumulus 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 ofandrogens by the theca cells, most notablyandrostendione, which are aromatized by granulosa cells to produceestrogens, primarilyestradiol. Consequently, estrogen levels begin to rise.
At this point, the majority of the group of follicles that started growth have died. This process of follicle death is known asatresia, and it is characterized by radicalapoptosis 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 thefollicular 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).[6]
In response to the rise of FSH, the antral follicles begin to secrete estrogen andinhibin, which have a negative feedback effect on FSH.[7] Follicles that have fewerFSH-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 thedominant follicle, will grow quickly and dramatically—up to 20 mm in diameter—to become thepreovulatory 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 thefollicular phase is about 1.5 mm per day (±0.1 mm), both in natural cycles and for any dominant follicle developing while takingcombined oral contraceptive pill.[8] Performingcontrolled ovarian hyperstimulation leads to a greater recruitment of follicles, growing at about 1.6 mm per day.[8]
By the end of the follicular (or proliferative) phase of the thirteenth day of the menstrual cycle, thecumulus oophorus layer of the preovulatory follicle will develop an opening, orstigma, and excrete the oocyte with a complement of cumulus cells in a process calledovulation. In natural cycles, ovulation may occur in follicles that are at least 14 mm.[9]
The oocyte is technically still a secondary oocyte, suspended in the metaphase II of meiosis. It will develop into an ootid, and rapidly thereafter into an ovum (via completion of meiosis II) only upon fertilization. The oocyte will now travel down one of thefallopian tubes to eventually be discharged through menstruation in the case that it is unfertilized or if it is not successfully implanted in theuterus (if previouslyfertilized).
The estradiol increases and triggers an ovulatory peak of LH (and FSH). This peak (through AMPc) activates the pro-inflammatory genes, which cause the break of the follicle wall and the oocyte gets out. The ruptured follicle will undergo a dramatic transformation into thecorpus luteum, a steroidiogenic cluster of cells that maintains theendometrium of the uterus by the secretion of large amounts ofprogesterone and minor amounts ofestrogen.
These two steps, while not part of folliculogenesis, are included for completeness. They are discussed in their entirety by their respective articles, and placed into perspective by themenstrual cycle article. It is recommended that these three topics be reviewed.
As with most things related to the reproductive system, folliculogenesis is controlled by theendocrine system. Five hormones participate in an intricate process of positive and negative feedback to regulate folliculogenesis. They are:
GnRH stimulates the release of FSH and LH from the anterior pituitary gland that will later have a stimulatory effect on follicle growth (not immediately, however, because only antral follicles are dependent on FSH and LH). When theca cells form in the tertiary follicle the amount of estrogen increases sharply (theca-derived androgen is aromatized into estrogen by the granulosa cells).
At low concentration, estrogen inhibits gonadotropins, but high concentration of estrogen stimulates them. In addition, as more estrogen is secreted, more LH receptors are made by the theca cells, inciting theca cells to create more androgen that will become estrogen downstream. This positive feedback loop causes LH to spike sharply, and it is this spike that causes ovulation.
Following ovulation, LH stimulates the formation of the corpus luteum. Estrogen has since dropped to negative stimulatory levels after ovulation and therefore serves to maintain the concentration of FSH and LH. Inhibin, which is also secreted by the corpus luteum, contributes to FSH inhibition. Progesterone, secreted by the corpus luteum, inhibits the follicular growth and maintains the pregnancy.
The endocrine system coincides with the menstrual cycle and goes through thirteen cycles (and thus thirteen LH spikes) during the course of normal folliculogenesis. However, coordinated enzyme signalling and the time-specific expression of hormonal receptors ensures that follicle growth does not become disregulated during these premature spikes.
Recently, two publications have challenged the idea that a finite number of follicles are set around the time of birth.[11][12] Renewal of ovarian follicles from germline stem cells (originating from bone marrow and peripheral blood) was reported in the postnatal mouse ovary. Studies attempting to replicate these results are underway, but a study of populations in 325 human ovaries found no supporting evidence for follicular replenishment.[4]
In 2010, researchers at theUniversity of Edinburgh determined that by the time women are 30 years old, only 10% of their non-growing follicles (NGFs) remain.[4] At birth, women have all their follicles for folliculogenesis, and they steadily decline untilmenopause.
As women (and mice) age, double-strand breaks accumulate in their primordial follicle reserve. These follicles contain primary oocytes that are arrested in prophase of the first cell division of meiosis. Double-strand breaks are accurately repaired during meiosis by searching for, and building off of, the matching strand (termed "homologous recombinational repair"). Titus et al.[13] (2013) found that, as humans (and mice) age, expression of four key DNA repair genes necessary for homologous recombinational repair declines in oocytes. They hypothesized that DNA double-strand break repair is vital for the maintenance of oocyte reserve, and that a decline in efficiency of repair with age plays a key role in the depletion of the ovarian reserve (ovarian aging).
In March 2025, Turkish researchers showed that Covid-19 vaccines lead to a reduction in primordial follicles in rats, reporting that mRNA vaccine group had an average of 42.40 primordial follicles, compared to 70.10 in inactivated vaccine group and 106.70 in unvaccinated group. The levels ofcaspase-3, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-beta1 were the highest in the mRNA group, and follicular anti-Mullerian Hormon (AMH) levels were lowest. Their study suggested that damage to primordial follicle pool occur because mRNA vaccine increases recruitment and caspase-dependent apoptosis in oocytes andgranulosa cells (CGs).[14]
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