Развитие и созревание первичных фолликулов яичника

Process of maturation of 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 immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles 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 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.

The primary role of the follicle is oocyte 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 of the human female contain many immature, primordial follicles. These follicles each contain a similarly immature primary oocyte. At puberty, 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. 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.

During ovarian follicle activation, 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 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 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, the basal lamina, and undergo cytodifferentiation to become the theca externa and theca 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 the antrum 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, and others designating them as preantral.

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 androgens by the theca cells, most notably androstendione, which are aromatized by granulosa cells to produce estrogens, primarily estradiol. 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 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. Performing controlled ovarian hyperstimulation leads to a greater recruitment of follicles, growing at about 1.6 mm per day. 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 to eventually be discharged through menstruation in the case that it is unfertilized or if it is not successfully implanted in the uterus (if previously fertilized). The estradiol increases and triggers and 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 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. 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.

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. (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).