Користувач:Coschan/Чернетка

Порядок змін в яєчниках.1 - Менструація 2 - Фолікул, що розвивається 3 - Зрілий фолікул 4 - Овуляція 5 - Жовте тіло 6 - Виродження жовтого тіла

У біології фолікулогенез — це дозрівання фолікула яєчника, щільно упакованої оболонки соматичних клітин, що містить незрілий ооцит. При фолікулогенезі низка дрібних первинних фолікулів прогресує до великих преовуляторних фолікулів, що частково відбувається під час менструального циклу.

На відміну від чоловічого сперматогенезу, який може тривати нескінченно довго, фолікулогенез закінчується, коли решта фолікулів яєчників не здатна реагувати на гормональні сигнали, які перед цим викликали дозрівання фолікулів. Це виснаження запасу фолікулів сигналізує про початок менопаузи.

Огляд

Основна роль фолікула — захист яйцеклітини. З усіх фолікулів, які утворюються в жіночому організмі, лише 0,1% з них примуть участь у овуляції, тоді як інші 99,9% зруйнуюсться (це явище називається фолікулярна атрезія). З самого народження жінки яєчники містять ряд незрілих, первинних фолікулів. Кожен із цих фолікулів містить подібний незрілий первинний ооцит. У період статевого дозрівання фолікули починають фолікулогенез, вступаючи в процесс росту, який закінчується овуляцією (процес, коли ооцит залишає фолікул), або атрезією (загибель клітин гранульозного фолікула).

Під час фолікулярного розвитку первинні фолікули зазнають ряд критичних змін, як гістологічно, так і гормонально. Спочатку вони змінюються на первинні фолікули, а пізніше на вторинні. Потім фолікули переходять до третинних, або антральних фолікулів. На цьому етапі розвитку вони стають залежними від гормонів, особливо ФСГ, що спричинює значне збільшення швидкості їх росту. Пізній третинний або доовуляторний фолікул розривається і виводить ооцит (який став вторинним ооцитом), закінчуючи фолікулогенез.

Діаграма фолікулогенезу, починаючи з преантрального (пізнього вторинного)

Фази розвитку

Фолікулогенез є безперервним, що означає, що в будь-який момент яєчник містить фолікули на різних стадіях розвитку. Більшість фолікулів гине і ніколи не завершує розвиток. Деякі з них повністю розвиваються, виробляючи вторинний ооцит, який виділяється розривом фолікула в процесі, який називається овуляцією.

Зростаючий фолікул проходить наступні стадії, які визначаються певними структурними характеристиками:

У більш широкому значенні, весь фолікулогенез, від первинного до преовуляторного фолікула, належить до стадії оотидогенезу оогенезу.

Стадія	Опис	Розмір
Початкова	Сплячий, невеликий, лише один шар плоских гранульозних клітин	Первинні фолікули мають діаметр близько 0,03-0,05 мм.
Первинна	Мітотичні клітини, кубоподібні гранульозні клітини	Діаметр майже 0,1 мм
Вторинна	Наявні тека-клітини, множинні шари клітин гранульози	Діаметр фолікула становить 0,2 мм
Рання третинна		Ранній третинний фолікул довільно розділений на п’ять класів. Фолікули класу 1 мають діаметр 0,2 мм, клас 2 — близько 0,4 мм, клас 3 — близько 0,9 мм, клас 4 — близько 2 мм, а клас 5 — близько 5 мм.
Пізня третинна	Повністю сформований антральний відділ, подальша цитодиференціація, новий прогрес	Фолікули класу 6 мають діаметр близько 10 мм, клас 7 — близько 16 мм, а клас 8 — близько 20 мм. Недомінантні фолікули зазвичай ростуть після класу 5, але рідко буває більше одного фолікула класу 8.
Преовуляторна	Зростання концентрації естрогену, всі інші фолікули зруйновані

Крім того, фолікули, що утворили антральний отвір, називаються антральними фолікулами або Граафовими фолікулами. Визначення різняться в тому, де цей зсув відбувається в таблиці, наведеній вище, причому одні вчені зазначають, що це відбувається при вступі на вторинну стадію, а інші вказують, що це відбувається при вступі до третинної стадії.

До переовуляторної стадії фолікул містить первинний ооцит, який затримується в фазі мейозу I. На пізній стадії переовуляції ооцит продовжує мейоз і стає вторинним ооцитом, залишившимся в метафазі II.

(a) The maturation of a follicle is shown in a clockwise direction proceeding from the primordial follicles. FSH stimulates the growth of a tertiary follicle, and LH stimulates the production of estrogen by granulosa and theca cells. Once the follicle is mature, it ruptures and releases the oocyte. Cells remaining in the follicle then develop into the corpus luteum. (b) In this electron micrograph of a secondary follicle, the oocyte, theca cells (thecae folliculi), and developing antrum are clearly visible. Electron microscopy images

Початкова

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 the human, the length of the ovarian cycle does not include this time.

The supply of follicles decreases slightly before birth, and to 180,000 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 of these follicles will ever reach the preovulatory stage. At menopause, 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, 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.

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 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

Antrum formation

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.

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 oophorous, 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.

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. Performing controlled ovarian hyperstimulation 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. 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 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 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.

Hormone function

As with most things related to the reproductive system, folliculogenesis is controlled by the endocrine system. Five hormones participate in an intricate process of positive and negative feedback to regulate folliculogenesis. They are:

• gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus
• two gonadotropins:
  • follicle-stimulating hormone (FSH)
  • luteinizing hormone (LH)
• estrogen
• 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

"Percentage of ovarian reserve related to increasing age. The curve describes the percentage of ovarian reserve remaining at ages from birth to 55 years, based on the ADC model. 100% is taken to be the maximum ovarian reserve, occurring at 18–22 weeks post-conception. The percentages apply to all women whose ovarian reserve declines in line with our model (i.e. late and early menopause are associated with high and low peak NGF populations, respectively). We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. DOI:10.1371/journal.pone.0008772.g005"

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 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.

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
• ovarian follicle activation
• granulosa cells
• fertilization
• menstrual cycle
• ovulation
• reproductive cycle
• spermatogenesis
• Follicular atresia
• Oocyte maturation inhibitor

Additional images

• 
  Section of the ovary. (#5 through #9 represent stages of folliculogenesis)
• 
  transitional primary follicle.

References

• Caglar G, Asimakopoulos B, Nikolettos N, Diedrich K, Al-Hasani S (2005). Recombinant LH in ovarian stimulation. Reprod Biomed Online. 10 (6): 774—85. doi:10.1016/S1472-6483(10)61123-6. PMID 15970010.
• Fortune, JE; Yang, MY; Muruvi, W (2010). Lucy, MC; Pate, JL; Smith, MF; Spencer, TE (ред.). The earliest stages of follicular development: follicle formation and activation. Soc Reprod Fertil Suppl. 67: 203—16. doi:10.7313/upo9781907284991.018. ISBN 9781907284991. PMC 5316466. PMID 21755674.
• Gougeon A (1996). Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 17 (2): 121—55. doi:10.1210/er.17.2.121. PMID 8706629.
• Gougeon A (1986). Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod. 1 (2): 81—7. doi:10.1093/oxfordjournals.humrep.a136365. PMID 3558758.
• van den Hurk R, Zhao J (2005). Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. Theriogenology. 63 (6): 1717—51. doi:10.1016/j.theriogenology.2004.08.005. PMID 15763114.
• Uzumcu, Mehmet; Zachow, Rob (2007). Developmental exposure to environmental endocrine disruptors: Consequences within the ovary and on female reproductive function. Reproductive Toxicology. 23 (3): 337—352. doi:10.1016/j.reprotox.2006.10.006. PMC 1950429. PMID 17140764.

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
• Folliculogenesis and Ovulation at gfmer.ch
• Reproductive Physiology at ufp.pt