Physiology, Ovulation

Ovulation is a physiologic process defined by the rupture of the dominant follicle of the ovary. This releases an egg into the abdominal cavity. It then is taken up by the fimbriae of 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 (ie, menstrual cycle). The follicular release follows the Follicular phase (ie, dominant follicle development) and precedes the luteal phase (ie, 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.

Structure

Genotypic females (XX) develop two ovaries that sit adjacent to the uterine horns. Each ovary is anchored to the uterus at the medial pole by the utero-ovarian ligament. 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 (ie, 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. At the onset of pubescence, the gonadotropic hormones began to induce the maturation of the primordial follicle, allowing for the 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.

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:

1. Gonadotropin-releasing hormone (GnRH) is a tropic peptide hormone made and secreted by the hypothalamus. It is a releasing hormone that stimulates the release of FSH and LH from the anterior pituitary gland through variations in GnRH pulse frequency. Low-frequency GnRH pulses are responsible for FSH secretion, whereas high-frequency pulses are responsible for LH secretion. During the Follicular phase of the Uterine cycle, estrogen secretion causes the Granulosa cells to autonomously increase their own production of estrogen, contributing to elevation in estrogen serum levels. This elevation is communicated to the hypothalamus and contributes to the increase in GnRH pulse frequency, eventually stimulating the LH surge that eventually induces the follicular rupture and release from the corpus luteum and luteinization of the granulosa cells, enabling the synthesis of progesterone in place of estrogen. Finally, the low levels of LH following the surge restart the FSH production by the slow-pulsation frequency of GnRH release.

2. Gonadotropin hormones are heterodimeric glycoproteins with alpha/beta subunits. The alpha subunit is common to all glycoproteins, including TSH (thyroid-stimulating hormone) and HCG (human chorionic gonadotropin hormone). The relationship between FSH and LH hormones is responsible for the process that induces follicular development, rupture, release, and endometrial reception or shedding. Disruption in the hormonal communication between the gonadotropin-releasing hormones, gonadotropic hormones, and their receptors can lead to anovulation or amenorrhea, leading to various pathologic sequelae as a consequence.

   1. Follicle-Stimulating Hormone (FSH) is a gonadotropin synthesized and secreted from the anterior pituitary gland in response to slow-frequency pulsatile GnRH. FSH stimulates the growth and maturation of immature oocytes into mature (Graafian) secondary follicles before ovulation. FSH Receptors are G-protein coupled receptors and are found in the Granulosa cells that surround developing ovarian follicles. The granulosa cells initially produce the estrogen needed to maturate the developing dominant follicle. After 2 days of sustained elevation of estrogen levels, the LH surge causes luteinization of the granulosa cells into LH receptive cells. This transition enables granulosa cells to respond to LH levels and produce progesterone.

      1. Estrogen is a steroid hormone that is responsible for the growth and regulation of the female reproductive system and secondary sex characteristics. Estrogen is produced by the granulosa cells of the developing follicle and exerts negative feedback on LH production in the early part of the menstrual cycle. However, once estrogen levels reach a critical level as oocytes mature within the ovary in preparation for ovulation, estrogen begins to exert positive feedback on LH production, leading to the LH surge through its effects on GnRH pulse frequency. Estrogen also has many other effects that are important for bone health and cardiovascular health in premenopausal patients, which will be discussed in another article.

   2. Luteinizing Hormone (LH) is a gonadotropin synthesized and secreted by the anterior pituitary gland in response to high-frequency GnRH release. LH is responsible for inducing ovulation, preparation for fertilized oocyte uterine implantation, and the ovarian production of progesterone through stimulation of theca cells and luteinized granulosa cells. Prior to the LH surge, LH interacts with Theca cells that are adjacent to granulosa cells in the ovary. These cells produce androgens, which diffuse into the granulosa cells and convert to estrogen for follicular development. The LH surge creates the environment for follicular eruption by increasing the activity of the proteolytic enzymes that weaken the ovarian wall, allowing for the passage of the oocyte. After the oocyte is released, the follicular remnants are theca and luteinized granulosa cells. Their function is now to produce progesterone, which is the hormone responsible for maintaining the uterine environment that can accept a fertilized embryo.

      1. Progesterone is a steroid hormone that is responsible for preparing the endometrium for the uterine implantation of the fertilized egg and maintenance of pregnancy. If a fertilized egg implants, the corpus luteum secretes progesterone in early pregnancy until the placenta develops and takes over progesterone production for the remainder of the pregnancy.