primordial follicles
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:''Although the process is similar in many animals, this article will deal exclusively with
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...
folliculogenesis.'' In
biology Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary i ...
, folliculogenesis is the maturation of the
ovarian follicle An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with t ...
, a densely packed shell of
somatic cells A somatic cell (from Ancient Greek σῶμα ''sôma'', meaning "body"), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Such cells compo ...
that contains an immature
oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The femal ...
. Folliculogenesis describes the progression of a number of small ''
primordial follicles :''Although the process is similar in many animals, this article will deal exclusively with human folliculogenesis.'' In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an ...
'' into large '' preovulatory follicles'' that occurs in part during the menstrual cycle. Contrary to male spermatogenesis, which can last indefinitely, folliculogenesis ends when the remaining follicles in the
ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
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 Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
.


Overview

The primary role of the follicle is
oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The femal ...
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 called follicular atresia). From birth, the
ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
of the human female contain a number of immature,
primordial follicles :''Although the process is similar in many animals, this article will deal exclusively with human folliculogenesis.'' In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an ...
. These follicles each contain a similarly immature
primary oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ge ...
. At
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a bo ...
, 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). 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 to tertiary, 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 a secondary oocyte), ending folliculogenesis.


Phases of development

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 called
ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...
. 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 of
ootidogenesis Oogenesis, ovogenesis, or oögenesis is the differentiation of the ovum (egg cell) into a cell competent to further develop when fertilized. It is developed from the primary oocyte by maturation. Oogenesis is initiated in the embryonic stage. O ...
of oogenesis. In addition, follicles that have formed an
antrum ''This is a disambiguation page for the biological term. For the 2018 horror movie, see Antrum (film)'' In biology, antrum is a general term for a cavity or chamber, which may have specific meaning in reference to certain organs or sites in the bod ...
are called
antral follicles An antral follicle, also known as Graafian follicle and tertiary follicle, is an ovarian follicle during a certain latter stage of folliculogenesis. Definitions differ in where the shift into an antral follicle occurs in the staging of follicul ...
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 Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately res ...
. During the late preovulatory stage, the oocyte continues meiosis and becomes a secondary oocyte, arrested in
metaphase II Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately res ...
.


Primordial

At 18–22 weeks post-conception, the cortex of the female ovary (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). 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. 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 Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
, 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 Ovarian follicle activation can be defined as primordial follicles in the ovary moving from a quiescent (inactive) to a growing phase. The primordial follicle in the ovary is what makes up the “pool” of follicles that will be induced to enter gr ...
, the granulosa cells of the primordial follicles change from a flat to a cuboidal structure, marking the beginning of the ''primary follicle''. The oocyte genome is activated and genes become transcribed. Rudimentary
paracrine signaling Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...
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. 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 The zona pellucida (plural zonae pellucidae, also egg coat or pellucid zone) is a specialized extracellular matrix that surrounds the plasma membrane of mammalian oocytes. It is a vital constitutive part of the oocyte. The zona pellucida first ap ...
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 The theca externa is the outer layer of the theca folliculi. It is derived from connective tissue, the cells resembling fibroblasts, and contains abundant collagen. During ovulation, the surge in luteinizing hormone increases cAMP which increases ...
and
theca interna Theca interna cells express receptors for luteinizing hormone (LH) to produce androstenedione, which via a few steps, gives the granulosa the precursor for estrogen manufacturing. After rupture of the mature ovarian follicle, the theca interna c ...
. 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 adjacent to the oocyte called the
antrum ''This is a disambiguation page for the biological term. For the 2018 horror movie, see Antrum (film)'' In biology, antrum is a general term for a cavity or chamber, which may have specific meaning in reference to certain organs or sites in the bod ...
designates the follicle as an antral follicle, in contrast to a so-called ''preantral follicle'' that still lacks an antrum. An antral follicle is also called a ''Graafian follicle''. Definitions differ as to which stage this shift occurs in, with some designating follicles in the ''secondary'' stage as ''antral'',Page 769
section "formation of the antrum" in:
and others designating them as ''preantral''.Page 76 in:


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 mitotis 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
androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
s by the theca cells, most notably androstendione, which are aromatized by granulosa cells to produce
estrogens Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
, primarily
estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
. 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''. ''Note: Many sources misrepresent the pace of follicle growth, some even suggesting that it takes only fourteen days for a primordial follicle to become preovulatory. Actually, the follicular phase of the menstrual cycle means 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 The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: proges ...
. Performing
controlled ovarian hyperstimulation Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval (egg col ...
leads to a greater recruitment of follicles, growing at about 1.6 mm per day.


Ovulation and the corpus luteum

By the end of the follicular (or proliferative) phase of the thirteenth day of the menstrual cycle, the cumulus oophorus layer of the preovulatory follicle will develop an opening, or ''stigma'', and excrete the oocyte with a complement of cumulus cells in a process called
ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...
. In natural cycles, ovulation may occur in follicles that are at least 14 mm. 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 the
fallopian tubes The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In ot ...
to eventually be discharged through menstruation in the case that it is unfertilized or if it is not successfully implanted in the
uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
(if previously
fertilized Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...
). The ruptured follicle will undergo a dramatic transformation into the corpus luteum, a steroidiogenic cluster of cells that maintains the endometrium of the uterus by the secretion of large amounts of progesterone and minor amounts of
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
. 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 the menstrual cycle article. It is recommended that these three topics be reviewed.


Hormone function

As with most things related to the reproductive system, folliculogenesis is controlled by the
endocrine system The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...
. Five hormones participate in an intricate process of positive and negative feedback to regulate folliculogenesis. They are: *
gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and release ...
(GnRH) secreted by the
hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
* two gonadotropins: ** follicle-stimulating hormone (FSH) **
luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...
(LH) *
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
* progesterone 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.


Number of follicles

Recently, two publications have challenged the idea that a finite number of follicles are set around the time of birth. 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. In 2010, researchers at the
University of Edinburgh The University of Edinburgh ( sco, University o Edinburgh, gd, Oilthigh Dhùn Èideann; abbreviated as ''Edin.'' in post-nominals) is a public research university based in Edinburgh, Scotland. Granted a royal charter by King James VI in 15 ...
determined that by the time women are 30 years old, only 10% of their non-growing follicles (NGFs) remain. At birth, women have all their follicles for folliculogenesis, and they steadily decline until
menopause Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
.


Depletion of the ovarian reserve

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. (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).


See also

*
ovarian follicle An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with t ...
*
ovarian follicle activation Ovarian follicle activation can be defined as primordial follicles in the ovary moving from a quiescent (inactive) to a growing phase. The primordial follicle in the ovary is what makes up the “pool” of follicles that will be induced to enter gr ...
* granulosa cells *
fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...
* menstrual cycle *
ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...
*
reproductive cycle In biology, a biological life cycle (or just life cycle or lifecycle when the biological context is clear) is a series of changes in form that an organism undergoes, returning to the starting state. "The concept is closely related to those of the ...
* spermatogenesis * Follicular atresia * Oocyte maturation inhibitor


Additional images

Image:Gray1163.png, Section of the ovary. (#5 through #9 represent stages of folliculogenesis) File:Primary follicle (transition).jpg, transitional primary follicle.


References

* * * * * *


External links


Morphology and Physiology of the Ovary at endotext.org

The ovary - folliculogenesis and oogenesis at nlm.nih.gov

Folliculogenesis Graphic Depicting Hormones Involved at anshlabs.com




{{Reproductive physiology F Animal developmental biology Human female endocrine system