Introduction

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.[1]

Development

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.[2][3][4][5][6]

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.[5][7][8]

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.[5][6][7]

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.[2][5][6][7][8]

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.[5][6][7]

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.[7]

Clinical Significance

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.[9]

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.[10]

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.[7][11][12]