Follicle Rupture and Ovulation
Women of reproductive age ovulate each month on or around the 14th day of their 28-day menstrual cycle when a mature egg from one ovary is released and then carried down through the fallopian tube to wait to be fertilized by its partner sperm.
Follicle monitoring can help identify follicles that are ready for ovulation. Our study determined that postponing intrauterine insemination until ruptured dominant follicles appeared to improve pregnancy rates significantly.
What Causes Follicles to Rupture?
At the start of a menstrual cycle’s follicular phase (the initial half), pituitary gland secretions of follicle-stimulating hormone cause somatic cells in an ovary to divide and form into an egg-containing structure called a follicle. Once mature, LH increases induce it to release an egg, which travels down its respective fallopian tube to be fertilized by sperm before dissolving naturally through natural body processes, with progesterone levels gradually decreasing as progesterone levels come down during this phase.
Ovulation is the cornerstone of female fertility. Studies have revealed that increasing chances of pregnancy when HCG injection is used to trigger ovulation as opposed to spontaneously expanding follicles; further, when an oocyte emerges from ruptured follicles fertilized immediately becomes significantly more significant than its chances of becoming pregnant spontaneously.
Understanding the mechanisms of ovulation is a cornerstone of research in gynecology. Follicle rupture is a multistep process that includes inflammation signaling, fluid pressure changes, and the release of fertilized eggs from an antral cavity. Studies have compared its spatiotemporal pattern during ovulation with that seen with pathological and physiological rupture events such as aneurysm rupturing.
Transcriptomic analysis of preovulatory follicles has revealed that several genes are upregulated prior to rupture, including fibroblast growth factor 4 and angiopoietin-like protein 4. Both of these have been linked with uneven intrafollicular pressure distribution in human follicles as well as rupture zone formation in porcine models.
Understanding the cellular dynamics that occur on a granulosa cell level during follicle rupture remains unclear, but proteolytic enzymes play an essential role. Discovering which proteases are responsible will shed more light on this complex process; studies on teleost fish such as the medaka have already begun uncovering such mechanisms.
How Long Does It Take for Follicles to Rupture?
Follicles must be capable of dissipating mechanical stress caused by their growth, and one way this is achieved is via the secretion of ECM proteins by their respective trophoblast. Proteolytic degradation by MMPs also appears to play an integral part.
Timing and localizing rupture sites within ovarian follicles at ovulation is essential to ensure successful fertilization of an egg; however, their mechanism remains unknown. One theory suggests vasoconstriction at the apex may play a critical role; an intravital multiphoton microscopy study measuring blood flow and diameter in follicles prior to expected ovulation found that blockade of vasoconstriction caused failure to rupture while restoration triggered rupture.
One study that made similar observations examined vascular remodeling and ECM degradation in medaka follicles that expressed either wild-type plasminogen activator I or it’s mutant that is deficient in tissue inhibitor of MMP-2b (Timp2b). The authors discovered that those with elevated Timp2b expression showed more rapid ECM degradation compared with those without this tissue inhibitor, while those lacking Timp2b did not. They speculated that increased proteolytic activity may facilitate localized degradation at the apex, leading to rupture and subsequent rupture.
Studies indicate that the dynamics of follicle rupture differ between systems, and more research must be conducted in order to identify its root cause. Although differences exist between contexts for rupture events, specific genes appear enriched across various rupture scenarios – these include c-Met, ER, and Akt, plus several growth regulators, notably Rgs2, Adam8 Lox, and Baz1a, are shared between systems.
These genes appear across various rupture data sets, suggesting they play an essential role in ECM degradation during follicle rupture. Further investigation of these genes could reveal unique pathways associated with this process or explain any overlap among different rupture systems.
How Long After Follicles Rupture Do Oocytes Extrude?
As follicles grow and mature, they produce an extracellular matrix consisting of hyaluronan and proteoglycans that help cumulus cell expansion and COC release from the mural granulosa layer. However, human cycles take a while before this process begins due to low LH levels in the preovulatory period; following an LH surge, however, cumulus cells become gradually more expanded and produce proteoglycan-binding protein, which facilitates detaching COC from the mural granulosa cell layer; once freed they escape antral cavity into peritoneal space where they are captured by oviductal fimbria for capture by fimbria or capture by antral fimbria for capture later.
Once COCs have been released from an oocyte, they undergo a process known as gonospermia. Oocytes that cannot survive this stage will die and be expelled through the vulva. Most of the remaining oocytes, however, are fertilized by sperm; consequently, fertility professionals have focused on increasing maturation rates as a way of improving clinical pregnancy rates.
Researchers have recently conducted studies using ultrasound technology to track ovulation in humans. They discovered that once an unfertilized egg has reached sufficient size, its protective covering of ovarian fluid will crack open, leading to its rupture and eventual release into ovulation.
Follicles rely on their tensile strength and the pressure exerted by blood flow within their surrounding ovarian tissue to resist rupture. As follicles approach rupture, their tensile strength starts reducing to where they no longer can resist external blood vessel pressure – pressure which is further compounded by LH and estrogen levels, which cause vasoconstriction within their surrounding vessels – before eventually breaking open and rupture occurring.
Follicle rupture in medaka fish is achieved through an extracellular matrix hydrolysis mechanism comprised of two steps, using both the urokinase-type plasminogen activator system and matrix metalloproteinase (MMP) systems. Pai1 expression and secretion are reduced during their 24-h spawning cycle, leading to new synthetic Plau1 being synthesized, which inhibits plasminogen activity before the MMP protease system becomes active due to drastically lower Timp2b levels.
How Long After Follicles Rupture Do Oocytes Remain Competent?
Long believed it has long been assumed that ovulation takes place when a dominant follicle ruptures and releases mature oocytes. Two small studies have reported cases in which dominant follicles rupture but do not release their mature oocytes1.1
Recent research using ultrasound-guided transvaginal aspiration as an aspiration method demonstrated it is possible to harvest large numbers of viable oocytes from the fluid of follicles that fail to release their eggs after ovulation, thus increasing the success of IVF treatment significantly. This discovery could transform fertility treatments.
The authors found that oocytes retrieved from post-rupture follicles were comparable in quality to those from pre-rupture follicles in terms of metaphase II stage development aspirated from each group, number of suitable quality blastocysts per group, and no discernable differences in chromosome content between groups.
Follicle monitoring was accomplished using transvaginal ultrasound (HI VISION Avius; Hitachi Medical Corporation of Tokyo, Japan), with levels of oestradiol E2 assessed each day. When follicles reached 16-18 mm diameter and had stories of oestradiol E2 higher than 190 pg/mL, buserelin acetate was administered via nose injection to trigger LH surge; then, 33-35 hours post-LH peak, scheduled oocyte retrieval procedures would begin.
Oocytes were incubated for 30 min at 5 mg/mL collagenase before receiving PG to enhance maturation. This treatment resulted in either WS-FL+ or WS-FL- phenotypes (Figure 4A).
Phenotype ratios observed for oocytes from follicles pretreated with collagenase were very close to those seen for those not pretreated, suggesting PG can trigger a switch and that maturation and rupture occur concurrently during in vitro ovulation processes. However, relative frequencies for intermediate phenotypes varied substantially across experiments due to variations in the batches used.