Follicle is a ovarian structure of one oocyte and surrounding granulosa (and later theca) cells.

Folliculogenesis is the development of ovarian follicles from primordial to tertiary under the stimulation of gonadotropins.

Primary follicles are ovarian follicles with a primary oocyte and one layer of cuboidal granulosa cells.

Primordial follicles are least developed ovarian follicles that consist of a single oocyte and a single layer of flat (squamous) granulosa cells.

Secondary follicles are ovarian follicles with a primary oocyte and multiple layers of granulosa cells.

Tertiary follicles are (also, antral follicles) ovarian follicles with a primary or secondary oocyte, multiple layers of granulosa cells, and a fully formed antrum.

Theca cells are estrogen-producing cells in a maturing ovarian follicle.

The Ovarian Cycle

The ovarian cycle is a set of predictable changes in a female’s oocytes and ovarian follicles. During a woman’s reproductive years, it is a roughly 28-day cycle that can be correlated with, but is not the same as, the menstrual cycle (discussed shortly). The cycle includes two interrelated processes: oogenesis (the production of female gametes) and folliculogenesis (the growth and development of ovarian follicles).

Folliculogenesis

Again, ovarian follicles are oocytes and their supporting cells. They grow and develop in a process called folliculogenesis, which typically leads to ovulation of one follicle approximately every 28 days, along with death to multiple other follicles. The death of ovarian follicles is called atresia, and can occur at any point during follicular development. Recall that, a female infant at birth will have one to two million oocytes within her ovarian follicles, and that this number declines throughout life until menopause, when no follicles remain. As you’ll see next, follicles progress from primordial, to primary, to secondary and tertiary stages prior to ovulation—with the oocyte inside the follicle remaining as a primary oocyte until right before ovulation.

Folliculogenesis begins with follicles in a resting state. These small primordial follicles are present in newborn females and are the prevailing follicle type in the adult ovary (Figure). Primordial follicles have only a single flat layer of support cells, called granulosa cells, that surround the oocyte, and they can stay in this resting state for years—some until right before menopause.

After puberty, a few primordial follicles will respond to a recruitment signal each day, and will join a pool of immature growing follicles called primary follicles. Primary follicles start with a single layer of granulosa cells, but the granulosa cells then become active and transition from a flat or squamous shape to a rounded, cuboidal shape as they increase in size and proliferate. As the granulosa cells divide, the follicles—now called secondary follicles (see Figure)—increase in diameter, adding a new outer layer of connective tissue, blood vessels, and theca cells—cells that work with the granulosa cells to produce estrogens.

Within the growing secondary follicle, the primary oocyte now secretes a thin acellular membrane called the zona pellucida that will play a critical role in fertilization. A thick fluid, called follicular fluid, that has formed between the granulosa cells also begins to collect into one large pool, or antrum. Follicles in which the antrum has become large and fully formed are considered tertiary follicles (or antral follicles). Several follicles reach the tertiary stage at the same time, and most of these will undergo atresia. The one that does not die will continue to grow and develop until ovulation, when it will expel its secondary oocyte surrounded by several layers of granulosa cells from the ovary. Keep in mind that most follicles don’t make it to this point. In fact, roughly 99 percent of the follicles in the ovary will undergo atresia, which can occur at any stage of folliculogenesis.

The ovary has two primary functions. First, the ovary produces hormones that drive the female reproductive system. Second, the ovary controls the development, selection, and release of a mature oocyte for fertilization. This process, known as ovarian folliculogenesis, begins while the female is in-utero. After puberty, primordial follicles can transform through a multi-step process into mature, pre-ovulatory follicles.

An ovarian follicle consists of a developing oocyte surrounded by one or more layers of cells called follicular cells. At the same time that the oocyte is progressing through meiosis, corresponding changes are taking place in the follicular cells. Primordial follicles, which consist of a primary oocyte surrounded by a single layer of flattened cells, develop in the fetus and are the stage that is present in the ovaries at birth and throughout childhood.

Beginning at puberty, follicle-stimulating hormone stimulates changes in the primordial follicles. The follicular cells become cuboidal, the primary oocyte enlarges, and it is now a primary follicle. The follicles continue to grow under the influence of follicle-stimulating hormone, and the follicular cells proliferate to form several layers of granulose cells around the primary oocyte. Most of these primary follicles degenerate along with the primary oocytes within them, but usually one continues to develop each month. The granulosa cells start secreting estrogen and a cavity, or antrum, forms within the follicle. When the antrum starts to develop, the follicle becomes a secondary follicle. The granulose cells also secrete a glycoprotein substance that forms a clear membrane, the zona pellucida, around the oocyte. After about 10 days of growth the follicle is a mature vesicular (graafian) follicle, which forms a "blister" on the surface of the ovary and contains a secondary oocyte ready for ovulation.

Ovarian follicular development begins while the female fetus is in-utero. During the fifth week of pregnancy, a female fetus's ovary contains about 500 to 1300 primordial germ cells. The primordial germ cells undergo mitosis, and by the twentieth week of pregnancy, the female fetus has approximately 6 to 7 million germ cells. Once mitosis is complete, the germ cells enter meiosis and arrest in meiotic prophase I, forming germ cell cysts. Peripartum, each germ cell cyst regresses to form a primordial follicle containing an oocyte and a single layer of nourishing granulosa cells. Many germ cells are lost during this process, and the female is born with one to two million primordial follicles. By the time she reaches puberty, approximately 400,000 to 500,000 primordial follicles remain. After menarche, approximately 1000 follicles are lost monthly. After 35 years of age, the rate of follicular loss increases.

There are two distinct phases of ovarian follicle development: gonadotropin-independent growth and gonadotropin-dependent growth. These phases also are known as pre-antral growth and antral growth, respectively. The gonadotropins are follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH are made and released from the anterior pituitary gland following stimulation from gonadotropin-releasing hormone (GnRH) from the hypothalamus. FSH controls follicular growth via granulosa cell proliferation, and LH controls ovulation.

Ovarian follicular development takes place in the peripheral cortex of the ovary. It takes approximately 1 year for a primordial follicle to mature before ovulation. Most of this time is spent in the gonadotropin-independent (pre-antral) phase. Gonadotropin-independent growth relies on local growth factors, beginning with the maturation of the primordial follicle, and ending before the follicle develops a fluid-filled space. Primordial follicles transition into primary follicles through oocyte enlargement and granulosa cell layer proliferation, which then starts to express FSH receptors. As primary follicles become secondary follicles, the simple cuboidal epithelium of the primary follicle transforms into the stratified columnar epithelium. The primary follicle stroma develops a blood supply and differentiates into the theca interna and theca externa. The theca interna develops LH receptors. The FSH and LH receptors enable the follicle to respond to their respective gonadotropins.

Further maturation of secondary follicles and selection of a dominant follicle for ovulation is gonadotropin-dependent. FSH binds to the FSH-receptors in the granulosa cell layer of the secondary follicle. In response to FSH stimulation, follicles continue to grow and develop a fluid-filled space. This space is referred to as an antrum and contains secretory material from the growing oocyte and granulosa cells. LH binds to the LH-receptors of the theca interna, resulting in the production of androgens. These androgens facilitate not only follicular growth but also promote follicular loss via apoptosis. As ovarian follicles mature, the larger follicles can use the enzyme aromatase to convert the androgens mentioned above into estrogen.

Increasing estrogen levels send a negative feedback signal to the hypothalamic-pituitary-adrenal (HPA) axis, decreasing the circulating levels of FSH. Large follicles remain sensitive to the decreasing levels of FSH. A large follicle is selected as the dominant follicle and continues to mature through a rapid proliferation of the granulosa and theca cells. The antrum also enlarges rapidly. The smaller follicles that were developing, but were not selected to be the dominant follicle during this cycle, degenerate because their small size decreases their sensitivity to FSH. Granulosa cells of the dominant preovulatory follicle develop high concentrations of LH receptors and become responsive to the LH surge. The LH surge is caused by further increases in circulating estrogen made by the pre-ovulatory follicle and results in ovulation. During ovulation, the follicle releases its mature oocyte for fertilization.

After ovulation, the empty follicle develops into the corpus luteum as the granulosa and theca cells become granulosa lutein cells and theca lutein cells, respectively. The corpus luteum secretes progesterone and estrogen to support implantation and early pregnancy. If implantation does not occur, the corpus luteum degenerates into a connective tissue structure known as the corpus albicans.

Abnormal follicular development is a hallmark of polycystic ovarian syndrome (PCOS), a disorder characterized by enlarged polycystic ovaries, abnormal menstrual bleeding, and increased androgen production. Compared to females without PCOS, ovaries of patients with PCOS have at least twice the number of growing pre-antral and antral follicles. Additionally, these follicles do not develop properly. Many follicles do not progress through the antral stage, accumulate excess fluid, lose their granulosa cell border, and degenerate into cystic structures. Patients with PCOS also have increased levels of LH, androgens, and insulin and decreased levels of FSH. The precise mechanism resulting in the cystic changes associated with PCOS remains unknown. The cystic changes can cause anovulatory infertility.

Premature ovarian failure is rare and most commonly presents as loss of ovarian reserve, defined as a decreased number of primordial follicles before 40 years of age. Patients present with absent menstruation and disrupted ovarian follicular development leading to symptoms of menopause and infertility. Premature ovarian failure also can present in patients who never reach menarche because of ovarian dysgenesis.

A proper understanding of ovarian follicular development is essential when counseling a patient regarding her fertility. Healthcare providers must understand and explain an assessment of her ovarian follicular reserve and the potential benefit of assisted reproductive technology (ART), including in-vitro fertilization and controlled ovarian hyperstimulation. As previously discussed, women under 35 years of age lose about 1000 primordial follicles per month, and this rate increases after 35 years of age. If a patient needs or desires ART, it is important to assess the patient’s ovarian reserve to maintain patient safety and define expectations. Ovarian reserve status is related to the production of antral follicles, which can be measured via transvaginal ultrasound. A decreased antral follicle count correlates to a lower ovarian reserve and decreased fertility. Patients with a smaller ovarian reserve are less likely to respond to ovarian stimulation, and women with a large ovarian reserve are at an increased risk of severe adverse effects. Knowledge of an individual patient's ovarian reserve will enable healthcare providers to determine a patient’s reproductive capability before and during ART and establish an appropriate ART regimen.