Ovulation is a physiologic process defined by the rupture and release of the dominant follicle from the ovary into the fallopian tube where it has the potential to become fertilized. The ovulation process is regulated by fluxing gonadotropic hormone (FSH/LH) levels. Ovulation is the third phase within the larger Uterine Cycle (i.e. Menstrual Cycle). The follicular release follows the Follicular phase (i.e. dominant follicle development) and precedes the Luteal phase (i.e. maintenance of corpus luteum) that progresses to either endometrial shedding or implantation. Follicular release occurs around 14 days prior to menstruation in a cyclic pattern if the hypothalamic-pituitary-ovarian axis function is well regulated.[1]
Structure
Genotypic females (XX) develop two ovaries that sit adjacent to the uterine horns. Each ovary is anchored at the medial pole by the utero-ovarian ligament to the uterus. The lateral ovarian pole is anchored to the pelvic sidewall by the infundibulopelvic ligament (i.e. suspensory ligament of the ovary), which carries the ovarian artery and vein. Each ovary contains 1 to 2 million primordial follicles that each contain primary oocytes (i.e. eggs) that can supply that female with enough follicles until she reaches her fourth or fifth decades of life. These primordial follicles are arrested in Prophase I of meiosis until the onset of puberty.[1] At the onset of pubescence, the gonadotropic hormones began to induce the maturation of the primordial follicle allowing for completion of Meiosis I forming a secondary follicle. The secondary follicle begins Meiosis II, but this phase will not be completed unless that follicle is fertilized. With each ovulatory cycle, the number of follicles decreases eventually leading to the onset of Menopause or the cessation of ovulatory function. Per each ovulation cycle, the average ovary loses 1,000 follicles to the process of selecting a dominant follicle that will be released. This process accelerates in an age-dependent manner as well. It is also a common thought that the right and left ovaries alternate follicular releases each month. [2][3][4]
Ovulation is regulated by the fluctuation between the following hormones. Tight regulation and controlled-changes between the following hormones are imperative for the development and release of an oocyte into the adnexal uterine structures.
Hormones involved in ovulation include:
The most common cause of female infertility in the United States is ovulatory dysfunction, in which a variety of hormonal factors interfere with the complex sequence of hormonal events required to trigger ovulation. Problems can occur at any point in this pathway (hypothalamus, pituitary, ovary) and can lead to failure to ovulate. The most common cause of chronic ovulatory dysfunction in the United States is Polycystic Ovarian Syndrome, or PCOS, which interferes with ovulation at multiple points.[7]
The Ovary is an oval-shaped organ about the size of an almond. It is organized into germ cells (i.e. oocytes) and somatic cells (i.e. granulosa, theca, and stromal cells) that work together to develop dominant mature follicles that can be released through ovulation for possible fertilization. The actions of the ovary are regulated primarily by FSH and LH hormones produced by the Anterior Pituitary gland as previously mentioned. Those hormones act as ligands to two receptor types found on somatic cells. The actions of these cells propagate the development of the adjacent germ cells to mature by providing an estrogen-rich environment.
The prepubertal ovary contains primordial follicles, which consists of an oocyte surrounded by a single layer of granulosa cells. Following puberty, the anterior pituitary begins to secrete FSH and LH in response to GnRH release from the hypothalamus, and the dormant cells in the ovary begin to secrete steroid hormones in response.
The hypothalamus secretes GnRH in a pulsatile fashion, which triggers FSH and LH release from the anterior pituitary. These, in turn, act on the granulosa and theca cells in the ovary to stimulate follicle maturation and trigger ovulation.
Follicular Development
Approximately 1,000 primordial follicles begin the process of maturation into primary follicles. At the onset of development, the granulosa cell layer that surrounds the oocyte increases in size and they begin estrogen production through FSH stimulation. FSH acts to initially propagate the beginning of estrogen synthesis; however, estrogen production becomes an autonomous process by granulosa cells. Thus, estrogen production and follicle development occur independently of FSH. The zona pellucida develops at this stage as well, and becomes the outermost portion of the oocyte, demarcating it from the granulosa cells. The zona pellucida in the protective casing through which sperm must penetrate in order to fertilize the egg following ovulation.
A subset of these primary follicles progress to the secondary follicle stage, during which the theca cell layer forms. Theca cells are stimulated by LH to synthesize androgens, which diffuse into the granulosa cells as estrogen precursors.
Next, the follicle develops a fluid-filled cavity surrounding the oocyte known as an antrum. At this stage, the follicle is referred to as an antral, or Graafian follicle. This stage can also be seen on ultrasound as a small, fluid-filled cyst on the ovary. The follicular phase of the menstrual cycle occurs when the antral follicle develops into a preovulatory follicle in preparation for ovulation. The follicular phase (i.e. follicle development) begins on day one which is characterized by the onset of menstruation and continues today 14 (i.e. ovulation) of a typical 28-day cycle. The antral follicle is dependent on FSH at this stage, and it begins to compete with the other developing follicles for FSH. The follicle that dominates this process is called the "dominant follicle" and all others will become atretic. The antral or "dominant" follicles secrete estrogen and inhibin, which exert negative feedback on FSH, thus "turning off" their neighboring antral follicles.
The majority of the follicles which began the process of maturation will undergo atresia (radical apoptosis of all cells within the follicle, including the oocyte) at some point during this process, leaving only one (rarely more) mature follicle to ovulate. If more than one follicle ovulates in a given cycle, this leads to non-identical multiple gestations, such as fraternal twins.
Ovulation
Ovulation occurs around day 14 of a typical 28-day cycle. Estrogen levels rise as a result of increased estrogen production by hormonally active granulosa cells within the follicle. One of the estrogen levels reach a critical point and remain at the level for 2 days, estrogen transitions from a negative feedback modulator of GnRH to a positive feedback modulator on the hypothalamus. This transition point leads to an increased frequency of GnRH secretion onto the anterior pituitary, leading to an LH surge. The LH surge increases intrafollicular proteolytic enzymes, weakening the wall of the ovary and allowing for the mature follicle to pass through.
The surge also causes the luteinization of thecal and granulosa cells forming the Corpus Luteum, which is responsible for progesterone synthesis levels. Once the follicle is released, it is caught by the fimbriae of the fallopian tubes. The oocyte remains in metaphase II of meiosis II unless fertilization occurs.
Luteal Phase
The luteal phase lasts from day 14 to 28 of a typical cycle. It begins with the formation of the corpus luteum and ends in pregnancy or luteolysis (destruction of the corpus luteum). FSH and LH stimulate what remains of the mature follicle after ovulation to become the corpus luteum. The corpus luteum grows and secretes progesterone and some estrogen, which makes the endometrium more receptive to implantation. If fertilization does not occur, progesterone/estrogen levels fall, and the corpus luteum dies forming the corpus albicans. These falling hormone levels stimulate FSH to begin recruiting follicles for the next cycle. If fertilization does occur, human chorionic gonadotropin (hCG ) produced by the early placenta preserves the corpus luteum, maintaining progesterone levels until the placenta is able to make sufficient progesterone to support the pregnancy.[10]
Anovulation Disorders are divided into 3 groups by the World Health Organization
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