Stages of follicular development

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Folliculogenesis is the process of development of ovarian follicles, from a reserve (in which they are found as inactive primordial follicles) established in the first years of life of the female mammal.

An ovarian follicle is a structure composed of somatic cells (follicular or granulosa cells, theca cells, and ovarian stromal cells) that surround the female germ cell (the oocyte). These cells undergo a series of morphological and functional transformations in the follicles of each cohort that develops cyclically in the ovary.

Ovarian Folliculogenesis
Ovarian follicles


Main changes during the Folliculogenesis process (in chronological order). (See full explanation in the video)


All the follicles that are part of the ovarian reserve are in the state of development known as «Primordial Follicle.» Then, when a group or cohort of follicles begins to develop, what happens is the following:

1. Follicular cells change from flat to cubic in shape, which make up a single layer (unilaminar follicle).

2. Cubic follicular cells proliferate forming several layers of cells. (multilaminar follicle).

3. A membrane or basal lamina arises around the granulosa cells; that delimits the follicle from the surrounding ovarian stroma. This originates from the secretions of the granulosa cells themselves.

4. The cells of the surrounding stoma begin to organize around the basal lamina, to form what will be the precursor cells of the Theca Follicularis.

5. Granulosa cells and oocytes secrete a mucoid substance that is deposited on the cell membrane of the oocyte; forming what is known as the zona pellucida. This is composed of several glycopoteins, grouped into four families: ZP1, ZP2, ZP3 and ZP4. The zona pellucida must be crossed by sperm before fertilization.

6. The granulosa cells begin to develop cytoplasmic processes that cross the zona pellucida. This, in order to establish direct contact with the plasma membrane of the oocyte; and thus be able to provide it with the necessary nutrients for its maturation.

7. In turn; The granulosa cells are also connected to each other; through gap junctions or nexus unions.

8. The follicular cells begin to produce follicular fluid, which generates the separation of these cells from the granulosa, due to the creation of cavities filled with fluid. These gradually join together until they form a single cavity called antrum.

9. At first, the antrum has a semilunar shape; but over time, it increases greatly in volume, due to a greater accumulation of follicular fluid.

10. The granulosa cells move toward the follicle wall, so that the oocyte is located eccentrically, but is held attached to the follicular wall by a stalk of granulosa cells. However, it is surrounded by a few granulosa cells called the cumulus oophorous . These allow us to actively contribute to the growth of the oocyte through the cytoplasmic projections that have been previously established, and that are now fully developed.

11. the cells of the follicular theca are already completely differentiated; and now form two concentric layers of cells:

Theca Externa: It is characterized by being made up of fibrous connective tissue cells, such as fibroblasts and collagen. This layer also contains smooth muscle cells or contractile filaments, which are also present in the ovarian stroma, and which could play some role in the contractility of the follicle for future expulsion of the oocyte.
Theca interna: contains a large number of blood vessels and secretory epithelial cells; since it is precisely here where ovarian steroidogenesis occurs.

Both layers of the Theca Follicularis receive abundant vascularization, although it is greater in the theca interna. Also, both contain lymphatic vessels and nerve endings.

12. The blood vessels present in the Theca do not cross the basal lamina that surrounds the granulosa cells; Therefore, the granulosa cells and the oocyte receive nutrients from the blood by diffusion, through the basal lamina. This is because the environment of the stratum granulosum is avascular.

13. The antral follicle reaches maturity, acquires a size of 10 millimeters or more, and is ready to ovulate.

The name given to each state of follicular development changes depending on the bibliographic source, but the process is the same:


Follicular development status

Denomination 1

Denomination 2

Denomination 3

Folículos primordiales

Primordial follicle

primordial follicle

primordial follicle

Folículos ováricos. Folículo unilaminar.

Growing follicle

Early primary follicle (unilaminar)

Primary follicle

Foliculo ovarico multilaminar

Primary follicle

Secondary follicle (multilaminar)

Secondary follicle (Preantral)

Foliculogénesis ovárica

Secondary follicle

Secondary follicle (early antral)

Tertiary (antral) follicle

Folículo antral

Tertiary follicle (antral – Graafian)

Large antral follicle

Preovulatory (Graafian) follicle

Preantral vs Antral follicles

However, regardless of the name of each state of follicular development (according to bibliographical variations), the determining fact that divides the process of folliculogenesis into two periods or stages is the formation of the follicular antrum. Before the formation of the antrum, the follicles are considered Pre-antral and after this event, the follicles are considered Antral. The importance of recognizing the existence of these two periods is that each of them is characterized by being influenced by very different hormonal states.

It is also important to highlight that the majority of early antral follicles undergo atretic degeneration; while some of them, under the cyclic stimulation of gonadotropins that occurs after puberty, reach the preovulatory stage.

Importance of follicular fluid


The follicular fluid performs various functions, such as:

a. Accumulate steroid hormones (mainly estrogens),  whose concentration can determine the fate of the follicle.

b. It is the vehicle for transporting the oocyte during ovulation.

c. Provide factors that, together with oviduct secretions, promote sperm training, fertilization and initial embryo development.

d. Prepare the follicle for the subsequent formation of the corpus luteum.

Folliculogenesis and ovulation


Not all primordial follicles (the state in which all the follicles of the ovarian reserve are found before developing) of a cohort that begins to develop in each cycle will become a Graafian or Preovulatory Follicle (maximum state of development prior to ovulation).

Some of the follicles reach more developed stages but the majority become atresia, since they are hormonally inhibited by the follicle(s) (depending on the species) selected. All of this is supported by cyclical changes in pituitary FSH and LH, so that only one reaches the preovulatory stage.

Then, all follicles that do not reach maximum Graafian or preovulatory follicle development (regardless of how far their development has gone) become atresia, which is known as follicular atresia.

The number of follicles that achieve ovulation, after a cohort of primordial follicles begins to develop in each ovarian cycle, depends on the species:

  • Monoestric species: Ovulation occurs in a single follicle from each cohort that grows in each ovarian cycle. The human species, horses and cattle are found here.
    The process followed by a group of follicles that begins to develop in each ovarian cycle is the following:

– Recruitment: When a number of follicles from the reserve are “selected” to be part of a cohort that will begin to develop at the same time. (This process happens in the follicles from the antral follicle state)
– Selection: One follicle has predominance over the others, due to the influence
hormonal that it exerts. This hormonal influence comes from ovarian steroidogenesis (see explanation below) and its interaction with pituitary hormones. (Complete explanation of this, in the article on ovarian steroidogenesis or in the article on follicular waves of the bovine estrous cycle).
– Dominance: The follicle of the selection stage is the only one that achieves ovulation, due to the hormonal influence it continues to exert. This is known as the Dominant follicle.

  • Poliestric Species: Ovulation of several follicles occurs at the same time. Here you can find sheep, goats, pigs, dogs and cats.
    After ovulation, the oocyte floats into the follicular fluid surrounded by the zona pellucida and part of the granulosa that forms the corona radiata, thus beginning the luteal phase.

Finally, all oocytes, fertilized or not, are transported to the uterus within 3 to 6 days after ovulation.

Importance of folliculogenesis

 

Folliculogenesis is essential for ovarian function and the propagation of the species because it causes the following two processes to occur during the phase of the female sexual cycle known as the follicular phase:

Gametogenesis (oogenesis): It consists of the initial development of the oocyte (primary); which involves the growth of the oocyte, along with an intense synthesis activity (since it synthesizes a large amount of ribonucleic acid-RNA). This happens at the same time as the development of the follicle that houses it. However, this remains a primary oocyte throughout the entire process of folliclegenesis, and its transformation into a secondary follicle occurs at the time ovulation takes place. (Link to Oogenesis Post).

Ovarian steroidogenesis: It includes synthesis of sexual steroid hormones such as: estrogens (Estrone (E1), 17-β Estradiol (E2), and Estriol (E3), androgens (Androstenedione and Testosterone) and progestins (Progesterone) This process occurs in the last stages of the dominant follicle (in the case of monotoca females), and after ovulation (during the formation and permanence of the corpus luteum); and it occurs due to the action of both the cells of the theca and the granulosa cells of the developing ovarian follicles (mainly the dominant one) and by the luteal cells of the corpus luteum, respectively. These hormonal changes exert an influence on the pituitary gland; which, in turn, also responds according to what is perceived, to generate the appropriate hormonal state for the next stage of the cycle, which leads to other events.

Both processes happen at the same time, in order for ovulation to take place.

Folliculogenesis in the ovarian cycle

Folliculogenesis occurs in the follicular phase of the female sexual cycle of most mammalian species.

However, in cattle, 2 or 3 cohorts of follicles also usually develop during the luteal phase of the cycle; This is called follicular surges. Despite this, only the wave of growing follicles that coincides with the hormonal conditions that occur during Proestrus will finally cause one of these follicles to develop enough to end in ovulation.

 
Bibliography

 

Bradley, G. K. (2014). Cunningham Fisología Veterinaria. Virginia. EE.UU: EL SEVIER SAUNDERS.

Filipiak , Y., Viqueira , M., & Bielli , A. (May de 2016). Development and follicular dynamics from fetal life until puberty in cattle. Scielo. Obtained from: https://acortar.link/BjcXaz

García Sacristán, A. (2018). Fisiología Veterinaria. Madrid. Tébar Florez.

Hafez, E. (2019). Reproducción e inseminación artificial en animales. McGrawHill.

Hsueh, A. J., Kawamura, K., Cheng, Y., & Fauser, B. J. (2015). Intraovarian Control of Early Folliculogenesis. PubMedCentral, 1-24. Obtained from:  https://goo.su/xvECG

Ortega Pérez, R., Palacios Espinosa, A., Espinoza, J. L., Valencia Méndez, J., & Aréchiga Flores, C. F. (Feb de 2017). Crecimiento folicular ovárico en animales domésticos: una revisión. Scielo. Obtained from: https://n9.cl/t7per

Pangas Stephanie  A., Rajkovic Aleksandar. (2015) Folliculogenesis. Ovarian folliculogenesis in mammals is a cyclic and dynamic process that involves dramatic change in the size and number of various cell types of the ovary. Science Direct. Obtained from: https://goo.su/u9bB6Jr

Vantman, B., & Vega, M. (May de 2010). Fisiología reproductiva y cambios evolutivos con la edad de la mujer. Science Direct. Obtained from: https://n9.cl/gjj59

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