Embryology, Ovarian Follicle Development


Article Author:
Emily Cox


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Veronica Takov


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Updated:
2/8/2019 12:06:51 AM

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, which contains 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 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 not only facilitate 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 to be 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 pre-ovulatory 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), which is a disorder characterized by enlarged polycystic ovaries, abnormal menstrual bleeding, and increased androgen production. When 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 be able to 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]


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Embryology, Ovarian Follicle Development - Questions

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Ovarian follicular development is a complex, multi-step process. As a primordial follicle undergoes this process to become a mature pre-ovulatory follicle, the follicle gains the ability to use the enzyme aromatase to convert androgens into estrogen. Where in the follicle does this occur?



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A 23-year-old white female presents to the clinic with concerns regarding her fertility. She states, "I heard the number of viable eggs a woman has decreases every year. I am worried because I started my period at 11 but am not ready to have kids now." Approximately how many follicles are present in both ovaries at puberty?



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A 32-year-old nulliparous African-American female made an appointment at a fertility clinic after struggling to conceive. She states that her primary care doctor drew blood at her last visit and called to say that the hormone that controls "egg development" was low relative to normal for women at the same point in their menstrual cycle. What structure releases this hormone?



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Germ cell production is a multi-step process that begins before a female is born. Throughout the process, many germ cells are lost. In what stage of development do germ cells freeze before transforming into primordial follicles?



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A 21-year-old overweight female presents to her primary care provider's office with complaints of irregular menstrual cycles and excessive facial hair. An ultrasound examination of her ovaries was completed. What type of ovarian follicle is expected to predominate in this patient?



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Embryology, Ovarian Follicle Development - References

References

Barnett KR,Schilling C,Greenfeld CR,Tomic D,Flaws JA, Ovarian follicle development and transgenic mouse models. Human reproduction update. 2006 Sep-Oct     [PubMed]
Drummond AE, The role of steroids in follicular growth. Reproductive biology and endocrinology : RB     [PubMed]
Sun YC,Sun XF,Dyce PW,Shen W,Chen H, The role of germ cell loss during primordial follicle assembly: a review of current advances. International journal of biological sciences. 2017     [PubMed]
Hirshfield AN, Overview of ovarian follicular development: considerations for the toxicologist. Environmental and molecular mutagenesis. 1997     [PubMed]
Macklon NS,Fauser BC, Follicle-stimulating hormone and advanced follicle development in the human. Archives of medical research. 2001 Nov-Dec     [PubMed]
Macklon NS,Fauser BC, Follicle development during the normal menstrual cycle. Maturitas. 1998 Oct 12     [PubMed]
Williams CJ,Erickson GF, Morphology and Physiology of the Ovary null. 2000     [PubMed]
Hillier SG, Gonadotropic control of ovarian follicular growth and development. Molecular and cellular endocrinology. 2001 Jun 20     [PubMed]
Chang RJ,Cook-Andersen H, Disordered follicle development. Molecular and cellular endocrinology. 2013 Jul 5     [PubMed]
Beck-Peccoz P,Persani L, Premature ovarian failure. Orphanet journal of rare diseases. 2006 Apr 6     [PubMed]
Sills ES,Alper MM,Walsh AP, Ovarian reserve screening in infertility: practical applications and theoretical directions for research. European journal of obstetrics, gynecology, and reproductive biology. 2009 Sep     [PubMed]
Fleming R,Seifer DB,Frattarelli JL,Ruman J, Assessing ovarian response: antral follicle count versus anti-Müllerian hormone. Reproductive biomedicine online. 2015 Oct     [PubMed]

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