The female reproductive system undergoes cyclical and structural changes throughout the menstrual cycle driven by the production of hormones by the ovary. As ovarian follicular development begins while the female fetus is in-utero, its proper understanding of the Ovarian reserve plays a critical role in estimating the ovarian reserve in a woman with infertility and counseling her regarding the line of treatment for subfertility. Diminishing ovarian follicles in the uterus is a common phenomenon in women during their mid to late thirties or even earlier, reflecting the lesser number of follicles and diminishing oocyte quality. Therefore, healthcare providers must assess ovarian follicular reserve resulting in voluntary or involuntary delayed childbearing and decide on the potential benefit of assisted reproductive technology (ART), including in-vitro fertilization and controlled ovarian hyperstimulation.
Ovarian follicles are small spheroid cellular aggregation sets found inside a woman’s ovaries. Filled with fluid that secretes hormones, these sacs influence different menstrual cycle stages. Women have approximately 200,000 to 300,000 follicles at the time of puberty, and each of them has the potential to release an egg cell (ovum) at ovulation for fertilization. Once every menstrual cycle with around 450-500 are ovulated during a woman’s reproductive lifetime, these eggs are developed.
The size and status of the follicles help assess fertility and fertility treatment. A pelvic ultrasound scan of your womb and ovaries, as well as an Anti-Mullerian Hormone blood test, can assess the size and number of follicles present on your ovaries, called an Antral Follicle Count. The follicle is the cell involved in the embryo obtained after fertilization. It is a functional anatomical structure that forms part of the ovary. The egg is the cell that matures in a tiny part of the inner wall of a follicle in each ovarian cycle under normal conditions. The follicles that don’t release a mature egg disintegrate through a process called atresia. About 99% of ovarian follicles can disintegrate at any stage of follicular development but never become mature enough to release an egg.
Furthermore, the follicle contains other cell types that produce estrogen required to develop egg maturation. Whether or not eggs are released can be determined in the first weeks of the life of the female embryo in each cycle from the first menstruation. Higher quality eggs are selected first as they become poorer with successive cycles; hence older women have more difficulty getting pregnant and have a higher rate of miscarriages.
Human ovaries generally produce a single dominant follicle that must complete all the steps in folliculogenesis on time to result in single ovulation. However, only a few among the multiple follicles in the ovary become dominant. This demonstrates the fundamental principle that folliculogenesis in mammals is a highly selective process. Here is a classification of follicles that can help understand follicular development.
An ovarian follicle undergoes several distinct phases before its ovum is released. Primordial follicles form in the fetal ovary in the first five months of development. They migrate into the developing gonad early in embryogenesis and form oogonia that proliferate by mitosis. Upon reaching sexual maturity, some of these Primordial follicles enlarge and mature to form primary oocytes to complete the first meiotic division to make gametes under the influence of follicle-stimulating hormone. The oocytes synthesize a coat called the ‘zona pellucida’ and cortical granules. They also obtain ribosomes, yolk, glycogen, lipid, and mRNA that will be used later on after fertilization to direct the early development of the embryo. Ova are formed post a second mitotic division. The oocyte in primordial follicles is surrounded by a single layer of flattened ovarian follicular epithelial cells called granulosa cells. It gets arrested in the last stage of prophase, known as dictyotene.
Primordial follicles get stimulated to become primary follicles at the beginning of each menstrual cycle. The oocyte enlarges, and the follicular cells are separated by the zona pellucida, a thin band of glycoproteins. Proteins on a sperm’s surface bind to specific glycoproteins in the zona pellucida. A follicle with two layers of follicular cells is called a primary follicle. These cells grow into a stratified epithelium known as the zona granulosa proliferate to form many layers surrounding the oocyte. This is followed by the enlargement of a thick glycoprotein layer known as zona pellucida at the late primary follicle stage. Then, the stroma around the follicle develops to form a capsule-like ‘theca.’ One out of all maturing follicles completes the maturation process each month. The remaining follicles degenerate into atretic follicles.
The primary follicle builds into a secondary follicle. The secondary follicles resemble the primary follicles but are larger and have more follicular cells. Small accumulations of fluid, called follicular fluid, happen in the intracellular spaces. These gradually merge to form an antrum rich in hyaluronan and proteoglycans. The surrounding granulosa cells are called the cumulus oophorus. The surrounding theca can be differentiated into the Theca Interna and Theca Externa. The androgens in Theca Interna are converted into estrogen by the granulosa cells.
The secondary follicle develops into a Graffian follicle that appears between the first meiotic division and completion of ovulation. The oocyte has become a secondary oocyte and starts its second meiotic division. The follicular fluid fills a single space, called the antrum, surrounded by the follicular cells called the membrana granulosa. The granulosa cells surrounding the oocyte project into the antrum and are known as the cumulus oophorus. The secondary oocyte is now surrounded by the zona pellucida and a layer of cells known as the corona radiata. After the ovum is expelled from the Graafian follicle, it enters the fallopian tube and into the oviduct. Next, the oocyte begins its second meiotic division, as far as metaphase II, but only if the ovum is fertilized.
After ovulation, the remaining cells of the Granulosa and Theca Interna form the corpus luteum. Its center contains the remains of the blood clot formed after ovulation. Granulosa cells enlarge, become vesicular, and are called Glanulosa lutein cells. These become folded, and the space between the folds is filled with Theca Interna cells surrounding the clot, whereas theca lutein cells are on their own, lying outside. The zona granulosa cells produce progesterone and a small amount of cholesterol. The corpus luteum also secretes estrogen and relaxin. The corpus luteum degenerates into corpus Albicans in case pregnancy doesn’t happen. The levels of estrogen and progesterone fall, allowing the release of FSH and LH. If pregnancy does occur, then the syncytiotrophoblasts of the placenta release human chorionic gonadotrophin, and the corpus luteum persists. Out of 20 primordial follicles that start developing in each cycle, only one makes it.
In the absence of fertilization, the cells of the corpus luteum remain active for around two weeks until the LH levels fall and the corpus luteum involutes to form the corpus Albicans. The secretory cells of the corpus luteum get phagocytosed by macrophages and are replaced by fibrous material. The corpus Albicans looks pale and continues to shrink until it forms a small scar on the side of the ovary.
Although several primordial follicles are triggered to continue development on each menstrual cycle, only one follicle completes development to release an ovum. At any stage of development, the other follicles can degenerate through a process called atresia. During atresia, granulosa cells undergo apoptosis and are replaced by fibrous material. The oocyte degenerates, and the basement that separates the oocyte from granulosa cells thickens to become the glassy membrane.
In a normal menstrual cycle, one follicle grows to contain one egg. The follicle gets bigger and ruptures at ovulation to release the egg. This happens around 14 days after the beginning of your menstrual cycle.
A woman can have an adequate or normal ovarian reserve which can count between 6-10, depending on the number of antral follicles. The ovarian reserve is considered low if the follicles count is less than 6 and high if the number is more than 12. It is more likely that women with low ovarian reserve do not respond to treatment, and women with high ovarian reserve exaggeratedly respond to treatment. In both cases, the treatment cycle becomes unsuccessful than in the instance of a normal follicular count.
The antral follicle test is a transvaginal ultrasound that measures the number of antral follicles present in the ovary. A doctor or a technician conducts the test using a probe, which is inserted into the woman’s vagina to examine and count the number of antral follicles on the ovaries. Follicles in ovary ultrasound can be seen despite measuring between 2 to 9 millimeters in diameter. The number of antral follicles can ascertain the number of eggs and the number of follicles that are too small to see and remain in the ovaries. Although this test is usually conducted on the third day of your menstrual cycle, in reality, it can be done at any time.
Older women have fewer antral follicles than younger women. Women between mid-20s and early 30s have around 12 to 30 antral follicles. Those between 35 and 40 have between 8 to 15, and those between 41 and 46 have anywhere between 4 to 10 antral follicles. Women with lesser than five antral follicles may need fertility treatments, like in vitro fertilization (IVF) with the aid of donor eggs to conceive.
Only one mature ovarian follicle or Dominant Follicle from the antral follicles is selected to “ovulate in a natural cycle.” This follicle can be differentiated from others in size and rapid growth. As part of a biological process, the other follicles disappear or die. The dominant follicle has an average diameter of 22 mm to 24 mm before ovulation occurs and can indicate whether ovulation will happen with ease.
An empty follicle syndrome is produced in very rare cases. It would not be egg retrieval after ovarian stimulation in IVF treatment in patients with adequate growth follicles and estradiol levels. An error in HCG administration, abnormal response to treatment, or impaired follicular mellowing can be the possible reasons for estimating or establishing their possible occurrence. This has been observed more frequently in women with a history of primary infertility and good follicle count. Despite being a rare event (<7%), its incidence increases with age. This, however, doesn’t imply that a patient has an exact fertility problem, and most may have a normal follicular mellowing and an adequate number of eggs.
A woman can get pregnant naturally with a single mature follicle as long as it releases an egg down the fallopian tube to meet the sperm. But if a woman is undergoing fertility treatment, it depends on the type of therapy and her age. For women using intrauterine insemination (IUI) and those aged below 40, one or two mature follicles are preferred. More follicles may not significantly increase the chances of getting pregnant, but it does raise your chance of having twins or multiples for women who happen to conceive. However, women over 40 using IUI may consider using ovulation-stimulating treatments for stimulating more mature follicles. It has been found that those women above 40 and up to four mature follicles tripled their odds of pregnancy without significantly raising their chances of multiples. Regardless of age, women undergoing IVF can be suggested to use fertility medications that produce more mature follicles. Hormone injections with follicle-stimulating hormone (FSH), luteinizing hormone (LH), or both are administered a couple of weeks beforehand to stimulate the ovaries. An ultrasound-guided needle is used during the IVF egg retrieval procedure to reach the ovaries and collect at least 10 or more eggs per cycle.
Women with PCOS have more antral follicles than women without PCOS. A woman with PCOS can have more than 30 antral follicles total. They produce above-average levels of the hormone testosterone, which obstructs ovulation. As the follicles struggle to release eggs, they fail to undergo ovulation. Women with PCOS can still get pregnant, but it can get delayed. Medications, such as metformin that contains ovulation-inducing drug Clomid or letrozole or IVF, can induce pregnancy. Losing weight, boosting vitamin D levels, and reducing stress may also help solve the problem. Although ovarian follicles can serve as an indicator of fertility, other factors like age, weight, health history, and even genetics can indicate the chances of pregnancy. An antral follicle count test can determine the chances of pregnancy at a certain point in time but not the entire duration of the reproductive cycle.
A diagnosis of follicle size and low ovarian reserves can be a matter of stress for most women. IVF with an egg donor is a possible path that not all couples agree or can take up. While ovarian follicle counts are an important indicator of fertility, one number doesn’t define you or can certainly predict the future of your fertility. Don’t be afraid to seek a second opinion on further fertility testing and diagnosis results if you’re unsure.
This post was last modified on January 11, 2022 10:33 am
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