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 it can also vary significantly from woman to woman and from cycle to cycle; vice versa, the next phase of the menstrual cycle, the luteal phase, 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 phase called primordial (immature), but some of them begin to develop in preovulatory follicles, each proceeding independently of the others.
The fundamental function of the follicles is to constitute the support for the oocytes, the egg cells enclosed within them.
The follicogenesi (the cycle of follicle maturation process) starts after puberty and may have resulted in the death of the follicle (atresia) or ovulation (release of the egg mature contained therein).
Contrary to themale spermatogenesis (which can last for an indefinite time), folliculogenesis ends when menopause is reached : the follicles in the ovaries are no longer sensitive to the hormonal signals that previously induced the follicular phase.
The follicular phase has two critical points beyond which the development of the follicle cannot proceed unless there are highly specific changes in both the structure of the follicle itself and in the composition of the surrounding environment. These critical points divide the follicular phase in three substeps different from the physiological point of view: preantrale phase , phase antral and pre-ovulatory phase .
The pre-antral phase has a variable duration, but is generally thought to last 3 to 5 days.
- When a follicle develops, the follicular cellsproliferate forming multiple layers around the oocyte and differentiate into the granulosa cells . The follicle from primordial thus becomes a primary follicle.
- During the pre-antral stage, the granulosa cells begin to secrete large quantities of glycoproteins which will form a thick membrane called zona pellucidaaround 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 theca cells . In this matrix, two layers are soon distinguished: an internal case (full of vessels, glandular) and an external case.
- The last modification of the follicle occurs towards the end of the pre-antral phase and consists in the appearance on the membranes of both types of follicular cells of gonadotropin receptors:
– luteinizing hormone ( LH )
receptors 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 next antral phase can only occur in the presence of gonadotropic hormones . Some follicles do not pass this stage and undergo atresia (degeneration with consequent death of the oocyte).
The preantral follicles enter this stage if there is an adequate concentration of luteinizing hormone ( LH ) and follicle-stimulating hormone ( FSH ) in the bloodstream , and if the follicle has acquired a sufficient number of receptors for these hormones.
The follicles that continue their development constitute a cavity filled with liquid called antrum , constantly expanding ( 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 the structure, associated with the formation of the antrum, corresponds to a functional transformation of the follicle which becomes a real endocrine gland, in charge of producing increasing amounts of androgens ( androstenedione and testosterone ), estrogens (especially estradiol ) and, in a later phase, progestogens .
As explained, follicular growth and development are promoted by both FSH and the estrogen secreted by the follicle itself. The plasma levels of FSH decrease gradually during the follicular phase. This tends to result in decreased 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 cells of the granulosa that surround the oocyte form the cumulus oophore , a small cord of cells that attacks the oocyte and the corona radiata (consisting of layers of granulosa cells surrounding the oocyte) to the follicle wall, now called Graafian follicle .
Towards the final stage of the antral phase, elevated estrogen and FSH levels promote another critical change: granulosa cells activate receptors for luteinizing hormone (LH), inducing the follicle to secretion of the new hormone and preparing the transition to the next phase of the ovarian cycle.
The duration of the antral phase is generally 8-12 days.
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. Blood levels of gonadotropins are much higher than normal values: there is a pre-ovulatory peak in the concentration of FSH and a real surge of LH (defined as LH-surge ).
The phase is defined as pre-ovulatory as it precedes the ovulation event shortly (lasts about 37 hours). This stage is called the phase of maturation or rupture of the germinal vesicle, as we basically witness the resumption of meiosis with the detachment of the secondary oocytefrom 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 follicles are processes subject to a delicate and precise balance between the levels of hormones in circulation and the production of their receptors in the follicular cells . If the levels of circulating hormones and the appearance of their receptors coincide, then follicular development can continue; conversely, if this condition is not reached, the follicles undergo degeneration and the formation of atretic bodies of the ovary .
Hormonal regulation is a fundamental control mechanism of the ovarian cycle.
The hormones who participate in the complex process of positive and negative feedback to regulate folliculogenesis are five:
- hormoneof release of gonadotropins (GnRH) secreted from the ‘ hypothalamus
- follicle-stimulatinghormone (FSH)
- luteinizing hormone(LH)
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 the primary follicles into the periodic phenomenon of ovulation , at least two positive feedback mechanisms must intervene:
- antral phase: exponential production of estrogen;
- preovulatory phase: exponential production of FSH and LH.