2.1: Ovaries and Ovarian Cycle

2.1.1 Ovaries

The ovaries are the female gonads responsible for the production of the female gametes (i.e., oocytes).

Normally, each female has two ovaries; each is about 2-3 cm long (i.e., almond-size). For details on the anatomy of the ovaries, please refer to Chapter 1.

Each ovary is both an exocrine (production of oocytes) and an endocrine (production of estrogen and progesterone) organ. The ovary is divided into an outer cortex and inner medulla (Figure 2.1.1, A and B, respectively). The ovarian medulla is composed of loose connective tissue with blood vessels, lymphatic vessels, and nerves (Figure 2.1.1, C). The ovary is suspended from the broad ligament of the uterus by the mesovarium (Figure 2.1.1, D), through which blood vessels enter and leave the ovary.

The exterior of the ovary is covered by a serous membrane, or serosa (Figure 2.1.1, E and F), composed of a simple cuboidal epithelium (mesothelium) overlying a band of dense connective tissue, the tunica albuginea (Figure 2.1.1, G and H). Usually, the serosa epithelium elsewhere is simple squamous epithelium. The serosal epithelium of the ovary was originally given the misnomer “germinal epithelium” because it was thought to be the site of germ cell formation.¹

Figure 2.1.1 (A) Ovarian cortex, magnified 10x: the cortex forms the outer zone of the ovary. It contains follicles, the corpus luteum, and their degenerating elements. These elements are follicles undergoing atresia and corpora albicantia (singular. corpus albicans). (B). Ovarian medulla, magnified 10x: the medulla occupies the center of the ovary and is composed of connective tissue containing blood vessels, lymphatic vessels, and nerves that supply the ovary. (C) Ovarian medulla at higher magnification (40x). (D) Mesovarium, magnified 10x: The ovary is suspended from the broad ligament of the uterus by the mesovarium, through which blood vessels enter and leave the ovary. (E). Ovarian serosa (magnified 10x): The serosa (serous membrane or visceral peritoneum) covering the ovary possesses a simple cuboidal, rather than a simple squamous, epithelium. This epithelium is referred to as the germinal epithelium. (F). Simple cuboidal epithelium of the ovarian serosa at higher magnification (400x). (G) Tunica albuginea, magnified 10x: A tunica albuginea of dense connective tissue forms an outer shell beneath the serosa. (H) Tunica Albuginea at higher magnification (400x).
Image Source: Images used with permission from Digital Histology. Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University.

The ovarian cortex is located underneath the tunica albuginea and is composed of the ovarian stroma, which forms the bulk of the adult ovary. The cortex hosts the ovarian follicles at different stages of development, as well as atretic follicles, corpus luteum, and corpora albicans (Figure 2.1.2, A, B).

Oocytes develop within the outer layer of the ovarian stroma. Each oocyte is surrounded by supporting cells. The ovarian follicle is composed of an oocyte and its supporting cells.

Figure 2.1.2 (A) Small follicles (arrows) are clustered beneath the tunica albuginea, while larger follicles (X) are located deeper in the cortex. 40x. (B) The surface of the ovary shows the position and size of the smallest follicles, the primordial and primary unilaminar follicles, located just beneath the tunica albuginea. Larger follicles (primary multilaminar and secondary follicles) are located deeper in the cortex. Follicles are epithelial structures that house developing oocytes, the germ cells. 100x.
Image Source: Images used with permission from Digital Histology. Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University.

2.1.2 Ovarian Cycle

The ovarian cycle is the set of predictable changes in a female’s oocytes and ovarian follicles. The ovarian cycle is approximately 28 days during a woman’s reproductive years and is correlated with the menstrual cycle. It is important to note that the ovarian cycle is different from the menstrual cycle. The ovarian cycle includes two interrelated processes: oogenesis (the production of female gametes) and folliculogenesis (the growth and development of ovarian follicles).

2.1.2.1 Oogenesis

Also known as gametogenesis, oogenesis starts during fetal life. The process begins with the ovarian stem cells, or oogonia (Figure 2.1.3). Oogonia are formed during fetal development and divide via mitosis (like spermatogonia in the testis). Unlike spermatogonia, oogonia form primary oocytes in the fetal ovary before birth. The primary oocytes are arrested in this stage of meiosis I until puberty. At the beginning of puberty, the primary oocyte resumes meiosis and continues until the woman is near menopause. The number of primary oocytes in the ovaries declines from one to two million in an infant to approximately 400,000 at puberty, to zero by the end of menopause.²

The release of an oocyte from the ovary is called ovulation. This process marks the transition from puberty into reproductive maturity for women. From this time and throughout the female reproductive years, ovulation occurs approximately every 28 days. A surge of luteinizing hormone before ovulation triggers the primary oocytes to resume meiosis. This results in the transition of a primary oocyte to a secondary oocyte. This meiotic cell division does not result in two identical cells. Because the cytoplasm is divided unequally, one daughter cell is much larger than the other. This larger cell is the secondary oocyte that eventually leaves the ovary during ovulation. The smaller cell is called the first polar body. If the first polar body completes meiosis, it will produce a second polar body. It will remain a first polar body if it does not complete meiosis. In either case, polar bodies undergo disintegration. Therefore, although oogenesis produces up to four cells, only one survives, which is the secondary oocyte.³

Figure 2.1.3 Oogenesis. The unequal cell division of oogenesis produces one to three polar bodies that later degrade, as well as a single haploid ovum, which is produced only if a sperm cell penetrates the secondary oocyte.
Image Source: Karve, Simantini. "Anatomy and Physiology of the Female Reproductive System." Human Physiology for Allied Health Professionals, (2022). This work is openly licensed via CC BY NC SA 4.0 Creative Commons License. Available from LibreText, Skyline College.

• How does the diploid secondary oocyte become an ovum—the haploid female gamete?

Meiosis of a secondary oocyte is completed only if a sperm succeeds in penetrating its barriers. Meiosis II then resumes, producing one haploid ovum that, at the instant of fertilization by a (haploid) sperm, becomes the first diploid cell of the new offspring (a zygote). Thus, the ovum can be thought of as a brief, transitional, haploid stage between the diploid oocyte and diploid zygote.

The larger amount of cytoplasm contained in the female gamete is used to supply the developing zygote with nutrients between fertilization and implantation into the uterus. Interestingly, sperm contributes only DNA at fertilization—not cytoplasm. Therefore, the cytoplasm and all of the cytoplasmic organelles in the developing embryo are of maternal origin. This includes mitochondria, which contain their own DNA. Scientific research in the 1980s determined that mitochondrial DNA was maternally inherited, meaning that you can trace your mitochondrial DNA directly to your mother, her mother, and so on back through your female ancestors.⁴

2.1.2.2 Folliculogenesis

Ovarian follicles are oocytes and their supporting cells. Folliculogenesis is the process of the development of ovarian follicles to prepare for ovulation (Figure 2.1.4). Approximately every 28 days, typically, one ovarian follicle undergoes ovulation. Follicular atresia is the death of ovarian follicles that can happen at any point during follicular development. A female infant will have one to two million oocytes within her ovarian follicles at birth. Because of follicular atresia, this number declines throughout life until it reaches zero around menopause. Based on the maturation stages of the follicles, there are different types of ovarian follicles: primordial, primary, secondary, and tertiary. The oocytes inside the follicles remain as primary oocytes until before ovulation.⁵

Figure 2.1.4 Folliculogenesis. (A) The maturation of a follicle is shown in a clockwise direction proceeding from the primordial follicles. FSH stimulates the growth of a tertiary follicle, and LH stimulates estrogen production by granulosa and theca cells. Once the follicle is mature, it ruptures and releases the oocyte. Cells remaining in the follicle then develop into the corpus luteum. (B) In this electron micrograph of a secondary follicle, the oocyte, theca cells (thecae folliculi), and developing antrum are visible. EM × 1100.
Image Source: Karve, Simantini. "Anatomy and Physiology of the Female Reproductive System." Human Physiology for Allied Health Professionals, (2022). This work is openly licensed via CC BY NC SA 4.0 Creative Commons License. Available from LibreText, Skyline College.

• Primordial Follicles

Folliculogenesis begins with follicles in a resting state. Follicles in the resting state are called primordial follicles. They are present in newborn females and are the dominant follicle type in the adult ovary (Figure 2.1.5, A). In primordial follicles, the oocyte is surrounded by a single flat layer of support cells called granulosa cells (Figure 2.1.5, B and C). Primordial follicles can remain in the resting state for years, even until just before menopause. After puberty, a few primordial follicles become primary follicles in response to recruitment signals.⁶

Figure 2.1.5 (A) Primordial follicles frequently appear in clusters near the surface of the ovarian cortex. These follicles develop in fetal ovaries during gestation and are seen in this position throughout the reproductive life of the female. Primordial follicles consist of a primary oocyte (B) surrounded by follicular cells, composed of a simple squamous epithelium and its underlying basement membrane (C). 400x. (B) Primary oocytes correspond to the same developmental stage as primary spermatocytes. However, diploid primary oocytes are formed before birth and arrest in the prophase of the first meiotic division at that time. A primary oocyte has a large nucleus, displaying dispersed chromatin, and a prominent nucleolus. (D) One follicle (red arrow) is in transition, lined with simple squamous follicular cells to the right of the arrow (primordial follicle) and by simple cuboidal follicular cells (primary unilaminar follicle) to the left of the arrow. 400x.
Image Source: Images used with permission from Digital Histology. Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University.

• Primary Follicles

These primary follicles are immature growing follicles. In the primary follicles, the primary oocyte is surrounded by a single layer of granulosa cells. These granulosa cells become active and increase in size and number as they proliferate, transitioning from a flat or squamous shape to a rounded, cuboidal shape. The primary unilaminar follicles are larger than primordial follicles; their follicular cells have increased in height to form a simple cuboidal or columnar epithelium (Figure 2.1.6, A). The primary oocyte has also increased in size from that present in the primordial follicle (Figure 2.1.6, B). Follicular cells continue to increase in volume and number, becoming a stratified epithelial layer and forming a primary multilaminar follicle (Figure 2.1.6, C). In the primary multilaminar follicle, the follicular cells are now termed granulosa cells (Figure 2.1.6, E), and the stromal cells surrounding the follicles differentiate into thecal cells (theca folliculi) (Figure 2.1.6, F). A thick glycoprotein layer develops between the oocyte and the zona granulosa, called the Zona Pellucida (Figure 2.1.6, G), and plays a critical role in fertilization.

Figure 2.1.6 (A) Primary unilaminar follicles. (B) Primary oocytes. Each primordial and primary follicle contains a primary oocyte. Each oocyte increases in diameter as the follicular cells increase in size and number. (C) A primary multilaminar follicle. (D) Stromal cells are located in the connective tissue surrounding the follicles. These connective tissue cells are multipotential and produce not only the connective tissue stroma of the ovary but also differentiate into the thecal layers surrounding advanced follicles. (E) Granulosa cells in a primary multilaminar follicle. (F) Stromal cells surrounding the follicle differentiate into the theca (theca folliculi). (G) Zona pellucida, a highly refractile, glycoproteinaceous layer, is prominent around the oocyte at this stage. 400x
Image Source: Images used with permission from Digital Histology. Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University.

• Secondary Follicles

The primary follicle develops into a secondary follicle (Figure 2.1.7). The secondary follicles look very similar to primary follicles, except that they are larger, they have more follicular cells, and there are small accumulations of fluid in the spaces between granulosa cells called follicular fluid (which provides oocytes with nutrients). These spaces gradually coalesce to form an antrum. The primary oocyte remains arrested in the prophase of the first meiotic division. Granulosa cells surrounding the antrum are now called the stratum granulosum. The granulosa cells surrounding the primary oocyte are called the cumulus oophorus (Greek for "egg-bearing heap"). The surrounding theca differentiates into two layers: the outer, more fibrous (spindle-shaped like cells) theca externa cells and the inner (rounded) theca internal cells that secrete follicular fluid, androgens, and progesterone in response to the luteinizing hormone (LH). The granulosa cells convert the androgens estrogen. Granulosa cells produce estrogen in response to follicular stimulating hormone (FSH); granulosa cells in pre-ovulatory follicles also respond to LH and produce progesterone (as will be explained in the section on hormonal control of the ovarian cycle).⁷

Figure 2.1.7 A secondary follicle; antral spaces (x), stratum granulosum (black rods), theca interna (blue rod), and theca externa (black arrow). Zona pellucida (blue arrowhead) is surrounding a primary oocyte. Granulosa cells around the primary oocyte and zona pellucida are called cumulus oophorus (200x.)
Image Source: Images used with permission from Digital Histology. Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University.

• Tertiary (Graffian) Follicles

Tertiary (Graffian) follicles are follicles in which the antrum becomes large and fully formed (Figure 2.1.8, A and B). Therefore, tertiary follicles are also called antral follicles. The first meiotic division is now completed, and the oocyte is now a secondary oocyte. The oocyte, zona pellucida, and follicular cells surrounding the oocyte (known as the corona radiata) are all expelled at ovulation and enter the fallopian tube. Once released, the oocyte begins its second meiotic division, as far as metaphase II. Several follicles can be at the same maturation stage at the same time. Most of the tertiary follicles undergo follicular atresia (Figure 2.1.8, C). The one that does not die will continue to grow and develop until ovulation. Around 99% of the ovarian follicles undergo atresia.⁸

Figure 2.1.8 (A) A tertiary or Graffian follicle; antrum (x); Stratum granulosal cells form a hillock surrounding the oocyte, termed the cumulus oophorus (black circles). 100x (B) The first row of cumulus cells outside the zona pellucida is the corona radiata (black arrows), stratum granulosum (green rods), theca interna (green arrows), and theca externa (blue arrow). 1000x. (C) Two different types of atretic follicles are seen. The antrum of an atretic secondary follicle (X) is visible; note the granulosal cells sloughed into the antrum. Each atretic follicle labeled with an arrow is composed only of its zona pellucida; the remainder of each follicle has degenerated. 100x.
Image Source: Images used with permission from Digital Histology. Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University.

Glossary Terms

Antrum

Fluid-filled chamber that characterizes a mature tertiary (antral) follicle

Corpora albicans

Nonfunctional structure remaining in the ovarian stroma following structural and functional regression of the corpus luteum

Corpus luteum

Transformed follicle after ovulation that secrets progesterone

Cytoplasm

Internal material between the cell membrane and nucleus of a cell, mainly consisting of a water-based fluid called cytosol, within which are all the other organelles and cellular solute and suspended materials

Endocrine

Groups of cells that release chemical signals into the intercellular fluid to be picked up and transported to their target organs by blood

Epithelium

Refers to layers of cells that line hollow organs and glands. It is also those cells that make up the outer surface of the body

Estrogen

Class of predominantly female sex hormones important for the development and growth of the female reproductive tract, secondary sex characteristics, the female reproductive cycle, and the maintenance of pregnancy

Exocrine

Group of epithelial cells that secrete substances through ducts that open to the skin or to internal body surfaces that lead to the exterior of the body

Fertilization

Occurs when sperm and an oocyte combine. Because each of these reproductive cells is a haploid cell containing half of the genetic material needed to form a human being, their combination forms a diploid cell. This new single cell is called a zygote

Follicle

Ovarian structure of one oocyte and surrounding granulosa (and later theca) cells

Folliculogenesis

Development of ovarian follicles from primordial to tertiary under the stimulation of gonadotropins

Haploid ovum

Contains a single copy of each chromosome with the sex chromosome always an X chromosome

Luteinizing hormone

Anterior pituitary hormone that triggers ovulation and the production of ovarian hormones in females, and the production of testosterone in males

Meiosis

Type of CELL NUCLEUS division, occurring during maturation of the GERM CELLS. Two successive cell nucleus divisions following a single chromosome duplication (S PHASE) result in daughter cells with half the number of CHROMOSOMES as the parent cells

Mesovarium

Extension of the peritoneum that connects the ovaries to the broad ligament

Oocytes

Cells that result from the division of the oogonium and undergoes meiosis I at the LH surge and meiosis II at fertilization to become a haploid ovum

Oogensis

process by which oogonia divide by mitosis to primary oocytes, which undergo meiosis to produce the secondary oocyte and, upon fertilization, the ovum

Ovaries

Female gonads that produces oocytes and sex steroid hormones (notably estrogen and progesterone)

Ovulation

Release of a secondary oocyte and associated granulosa cells from an ovary

Primordial follicles

Least developed ovarian follicles that consist of a single oocyte and a single layer of flat (squamous) granulosa cells

Progesterone

Sex hormone important in regulating the reproductive cycle in those with ovaries and the maintenance of pregnancy

Stroma

Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere

Thecal cells

Estrogen-producing cells in a maturing ovarian follicle

Tunica albuginea

Fibrous-elastic sheath of connective tissue that surrounds the shaft and glans of the clitoris

Zygote

Fertilized OVUM resulting from the fusion of a male and a female gamete

 

Footnotes

1. Karve, Simantini. "Anatomy and Physiology of the Female Reproductive System." Human Physiology for Allied Health Professionals, (2022). This work is openly licensed via CC BY NC SA 4.0 Creative Commons License. Available from LibreText, Skyline College.
2. Karve, 2022.
3. Karve, 2022.
4. Lang, Damaris-Lois. "Anatomy and Physiology of the Female Reproductive System." Chapter 43, Bio 140 Human Biology I, (2022). Hostas Library. CC BY NC 4.0
5. Karve, Simantini, 2022
6. Karve, Simantini, 2022
7. Paxton, Steve, Michelle Peckham, Adele Knibbs, Steve Paxton, Adele Knibbs, and Michelle Peckham. "Female Reproductive system." The Leeds Histology Guide, (2003). University of Leeds.
8. Paxton et al., 2003.

Image Acknowledgements

• Karve, Simantini. "Anatomy and Physiology of the Female Reproductive System." Human Physiology for Allied Health Professionals, (2022). This work is openly licensed via CC BY NC SA 4.0 Creative Commons License. Available from LibreText, Skyline College.
• Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University.