Changes in structure and size of a follicle that lead to a mature oocyte happen in a process of folliculogenesis. It is a process that takes approximately one year in women, and it includes growth of a recruited primordial follicle that develops into a specialized Graafian follicle which will either ovulate to give a mature oocyte or die by atresia.
The mechanisms that regulate folliculogenesis are controlled by varying concentrations of hormones and follicle growth factors, at the endocrine level they are regulated by the central nervous system, anterior pituitary, and ovary cascade system. It is important to mention the synergy of these two control systems, where follicle growth factors can increase or decrease the action of certain hormones at the local level – the autocrine or paracrine control system. Interestingly, very similar mechanisms control early embryogenesis and blastocyst implantation.
It was examined spatiotemporal regulation of mentioned signals and also confirmed that hypothalamic-pituitary-gonadal hormones regulate folliculogenesis, follicular quiescence, ovulation, follicular atresia, and corpus luteal functions. After conception and in early embryo development, autocrine and paracrine signaling becomes increasingly important, and these signals are crucial for synthesis of human chorionic gonadotropin (hCG) which is a proof of embryo existing in female reproductive system. This hormone ultimately has an effect, upon blastocyst arrival in the uterus, on tissue remodeling and supports controlled invasion of the blastocyst in the endometrium.
With regard to the structural changes, human folliculogenesis can be divided into four main stages, which include initiating of follicle growth, early follicle growth, selecting of one follicle from a pool of selectable follicles, and the maturation of the preovulatory follicle. We can see that primordial, transitory, and small primary follicles make up the ovarian reserve, and the initiation of follicle growth begins when the oocyte nucleus reaches a critical diameter of 19 mm.
After entering the follicle growth phase, granulosa cells proliferate and the oocyte grows at the quickest rate so follicles become secondary follicles with multiple layers of granulosa cells and are around 2 mm in diameter. Selectable follicles measure from 2 to 5 mm and their number ranges from 3 to 11 in an ovary of women 24-33 years of age. It was shown that the selected follicle is the one that is the healthiest, grows faster than the other ones, and is the most sensitive to follicle-stimulating hormone (FSH). From the time of selection to ovulation, the selected follicle rapidly changes in size from approximately 6 mm up to 18 mm and more, and it is important to point out that in the mid-follicular phase the preovulatory follicle becomes highly vascularized through theca. Theca cells have a very important role in folliculogenesis – they synthesize androgens, connect granulosa cells and oocyte during development, and provide support for a growing follicle. They are, to simplify, an outer layer of the follicle and have their origin in stromal tissue surrounding the primordial follicle. They are specialized cells that are recruited to surround an activated follicle and provide structural support and acquire a capillary network.
Regarding the recruitment of follicles into later stages of development, there are two types there: initial and cyclic recruitment. Initial recruitment involves primordial follicles that aren’t under influence of hormones, they remain dormant and this happens continuously throughout life after follicle formation and oocytes have just started to grow. Cyclic recruitment involves antral follicles in growth phase that are under FSH influence, start their recruitment after onset of puberty with grown oocytes, and can undergo apoptosis as a mechanism of cellular death if not selected to reach maturity and ovulate.
Transcriptome analysis (mRNA expression) in cumulus cell can indicate quality of the environment the oocyte was exposed to while maturing and give rise to some biomarkers that can be an indicator of oocyte and later embryo fitness resulting in healthy pregnancies.
We can say that in terms of structural changes, follicular antrum or cavity certainly has very expansive growth and makes the majority of volume of preovulatory Graafian follicle. The process of follicular antrum and fluid formation was described in a way that granulosa cells produce hyaluronan and proteoglycan versican generates osmotic gradient that draws fluid from thecal vasculature.
When speaking of follicular fluid composition and general follicle as a microenvironment for a developing oocyte, it is important to note the existence of oxidative stress in the form of reactive oxygen species (ROS) as products of metabolism within the follicle. Melatonin, generally known as a pineal gland secrete that regulates circadian rhythm and reproduction, is found to be an excellent free radical scavenger in the ovarian follicle.
Oocytes maintain a close relationship throughout the entire follicular development, oocytes form a specialized membrane system that provides a cytoplasmic scaffold inside the zona pellucida and eases the metabolic exchange between oocytes and follicular cells and, lastly, such a structure can be called a syncytium because of the existing complex that finely modulates the oocyte growth.
Ovulation is a process of breaking the outer layer of a mature Graafian follicle releasing the follicular fluid with a mature oocyte within a cumulus oocyte complex (COC). A research has shown that ovulation characteristics were age dependent and that women under the age of 29 have ovulations alternating between two ovaries in consecutive cycles and as the age increases there is a higher chance of ovulation in the same ovary in two consecutive cycles.
After ovulation and exit of a mature oocyte, residual follicular cells form the corpus luteum with a main task of high amounts of progesterone production in order to support a possible pregnancy.
After luteinizing hormone (LH) induced ovulation, follicular cells stop dividing and undergo terminal differentiation to luteal cells that produce progesterone. There are two more structural changes that lead to the formation of corpus luteum – tissue remodeling that includes changes in extracellular matrix composition that supports basic cellular processes and vascularization which is development of capillaries from pre-existing blood vessels in such a way that each cell of corpus luteum is in direct contact with several capillaries giving corpus luteum one of the highest blood rates in the organism.
It is important to preserve the existing pregnancy until placenta is fully developed. In case that pregnancy does not happen, corpus luteum stops with progesterone production and luteal cells die through apoptosis, tissue disintegrates, and changes result in a gland formed of connective tissue called corpus albicans.