The follicular phase (or proliferative phase) is the first phase of the ovarian cycle: it begins with the first day of the menstrual cycle and ends with ovulation. The duration of this phase is on average 14 days, but can also vary considerably from woman to woman and from cycle to cycle; vice versa, the next phase of the menstrual cycle, the luteinic one, is more stable in terms of duration, which is always equivalent to 14 days.
Inside the ovaries there are numerous follicles at different stages of development. Most of these are in a defined primordial (immature) phase, but some of them begin to develop into pre-ovulatory follicles, each proceeding independently of the others.
The fundamental function of the follicles is to provide support for the oocytes, the egg cells enclosed within them.
Contrary to male spermatogenesis (which can last for an indefinite time), folliculogenesis ends on reaching menopause : follicles in the ovaries are no longer sensitive to hormonal signals that previously induced the follicular phase.
The follicular phase presents two critical points beyond which the development of the follicle cannot proceed unless there are highly specific changes both in the structure of the follicle itself and in the composition of the surrounding environment. These critical points divide the follicular phase into three different phases from a physiological point of view: the preantral phase, the antral phase and the pre-ovulatory phase .
Early Phase
The preantral phase has a variable duration, but is generally thought to last from 3 to 5 days.
- When a follicle develops, the follicular cells proliferate forming multiple layers around the oocyte and differentiate into granulosa cells . The primordial follicle thus becomes a primary follicle.
- During the preantral stage, the granulosa cells begin to secrete large quantities of glycoproteins which will form a thick membrane called the pellucid zone around the oocyte and the granulosa. The exchange of metabolites with the oocyte is ensured by the communicating junctions located in the cytoplasmic extensions between the oocyte and the surrounding granulosa cells.
- Some specific connective tissue cells (ovarian stroma) differentiate to form the outer layer of the cells of the theca . In this matrix two layers are soon distinguished: an internal case (rich in vessels, glandular) and an external case.
- The last modification of the follicle occurs towards the end of the preantral phase and consists in the appearance on the membranes of both types of follicular cells of gonadotropin receptors: - luteinizing hormone receptors ( LH ) on thecal cells
- follicle stimulating hormone ( FSH ) receptors on granulosa cells.
The presence of these receptors is essential for the continuation of oogenesis, as the transition to the subsequent antral phase can only take place in the presence of gonadotropic hormones. Some follicles do not pass this stage and undergo atresia (degeneration with consequent death of the oocyte).
Antral Phase
Preantral follicles enter this stage if an adequate concentration of luteinizing hormone ( LH ) and follicle-stimulating hormone ( FSH ) is present in the bloodstream, and in the event that the follicle has acquired a sufficient number of receptors for these hormones.
The follicles that continue their development constitute a cavity full of liquid called antrum, in constant expansion ( early antral stage ). At this point the follicles are called secondary follicles ; in a typical ovarian cycle about 15-20 follicles enter this stage of development. After about seven days, one of these follicles ( dominant follicle ) is selected to complete its development, while the remaining secondary follicles will undergo atresia.
The change in structure, associated with the formation of the antrum, corresponds to a functional transformation of the follicle that becomes a real endocrine gland, responsible for producing increasing amounts of androgens (androstenedione and testosterone), estrogens (especially estradiol) and, in one next step, progestins.
As explained, follicular growth and development are promoted by both FSH and estrogen secreted by the follicle itself. Plasma FSH levels gradually decrease during the follicular phase. This tends to cause a decrease in estrogen secretion. The selection of the dominant follicle depends on its ability to produce adequate levels of estrogen in the face of falling FSH levels.
The dominant follicle continues its development in the late antral stage : some granulosa cells that surround the oocyte go to make up the cumulus oophorus, a small cord of cells that attacks the oocyte and the radiated corona (consisting of layers of granulosa cells surrounding the oocyte) to the follicle wall, now called the Graafian follicle .
The duration of the antral phase is generally 8-12 days.
Pre-ovulatory phase
To enter the pre-ovulatory phase, the mature antral follicle must find an adequate concentration of FSH and LH in the surrounding environment, so that it does not undergo atresia. The blood levels of gonadotropins are much higher than the normal values: a pre-ovulatory peak is observed in the concentration of FSH and a real wave of LH (defined as LH-surge ).
The phase is defined pre-ovulatory as it slightly precedes (lasts about 37 hours) the ovulation event. This stage is defined as the stage of maturation or rupture of the germinal vesicle, as it basically assists in the resumption of meiosis with the detachment of the secondary oocyte from the wall, which is free to float in the antral fluid, together with the radial crown that covers it . In this third stage of the follicular phase of the ovarian cycle, the pre-ovulatory follicle considerably increases its volume.
Hormonal regulation of the follicular phase
During the follicular phase of the ovarian cycle, the growth and differentiation of the follicles are processes subjected to a delicate and precise balance between the levels of circulating hormones and the production of their receptors in the follicular cells. If the levels of circulating hormones and the appearance of their receptors coincide, then the follicular development can continue; vice versa, if this condition is not reached, the follicles undergo degeneration and formation of atretic ovary bodies.
Hormonal regulation is a fundamental mechanism for controlling the ovarian cycle.
There are five hormones that participate in the complex process of positive and negative feedback to regulate folliculogenesis:
- Gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus
- follicle stimulating hormone (FSH)
- luteinizing hormone (LH)
- estrogen
- progesterone
The hormones produced by the pituitary gland (FSH and LH) and the hormones produced by the ovary (estrogen and progesterone) have antagonistic effects (negative feedback control).
At the same time, to transform the continuous production of primary follicles into the periodic phenomenon of ovulation, at least two positive feedback mechanisms must intervene:
- antral phase: exponential production of estrogens;
- preovulatory phase: exponential production of FSH and LH.
