Follicles - Anatomy & Physiology

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Introduction

The follicle is the functional unit of the ovary containing both gametes (Oocyte) and endocrine cells (Granulosa and Theca cells). A female is born with all the primordial follicles it is ever going to have i.e Primordial Follicles do not divide anymore, they either develop further into primary, secondary, and tertiary follicles or they degenerate. Therefore the number of follicles declines with age as follicles develop and degenerate during the oestrus cycle. When the supply of follicles is depleted then reproductive senescence occurs. In humans this phenomenon is known as "The Menopause". Prior to ovulation, oogenesis and hormone production both occur in the follicle. The process of follicular growth is known as Folliculogenesis.

General Structure

Histological Section of the Ovary showing Granulosa and Theca Cells of a Follicle- Courtesy of J.Bredl, Copyright RVC 2008

• Made up from two cell types; Granulosa cells and Theca cells aranged in two different layers.
  • The Granulosa cell layer is the inner cell layer found closest to the oocyte
  • The Theca cell layer is the outer cell layer

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Follicular Development (Folliculogenesis)

Primordial Follicle

Histological Section of the Ovary showing Characteristics of the Primordial Follicle- Courtesy of J.Bredl, Copyright RVC 2008

• Smallest and most immature follicle
• One primary oocyte surrounded by a Single layer of squamous cells known as pre-granulosal cells.
• Development from the primordial follicle to the primary follicle is characterized by:
  • Increase in the size of the oocyte
  • The surrounding of the oocyte by a single layer of cuboidal granulosa cells which are capable of hormone production.
  • Separation of the oocyte from the granulosal cells by a thick layer of material known as the zona pellucida.
• This development is driven by Gdf9 and BMP15. Knockouts of these genes result in the failure of primordial follicles to develop into primary follicles. These are normally found within the oocyte itself.

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Primary Follicle

Histological Section of the Ovary showing Characteristics of the Primary Follicle- Courtesy of J.Bredl, Copyright RVC 2008

• Oocyte surrounded by a single layer of follicular cuboidal cells.
• The primary follicle will develop into a secondary follicle.
  • Granulosa cells proliferate into multiple layers and at the end of this the oocyte is fully grown.
• Events that characterize this transition are:
  • Thecal layer becomes organised into the Theca Interna and the Theca Externa
  • Vascularisation of the theca
• If gonadotrophins (LH and FSH) are removed, this transition still takes place.

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Secondary Follicles

Histological Section of the Ovary showing Characteristics of the Secondary Follicle- Courtesy of J.Bredl, Copyright RVC 2008

• The oocyte has developed a thick translucent glycoprotein layer called the Zona Pellucida.
• Oocyte surrounded by two or more layers of follicular cuboidal cells. These cells differentiate into the inner Granulosa cells and outer Theca cells.
• Connective tissue cells surrounding the granulosa cells differentiate to form the layers of theca cells which produce androgens.
  • Androgens act as substrates for synthesis of oestrogens by granulosa cells.
• Granulosa cells secrete

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Tertiary/Antral Follicles

Histological Section of the Ovary showing Characteristics of the Tertiary/Antral/Graafian Follicle- Courtesy of J.Bredl, Copyright RVC 2008

• The innermost cells of the Granulosa layer become firmly attached to the Zona Pellucida and are known as the Corona Radiata. The outermost Granulosa cells become attached to the basement membrane surrounding them and become known as the Theca Folliculi.
• Granulosa cells secrete fluid which accumulates within the follicle forming an Antrum.
• Theca cells become organised into Theca Interna and Theca Externa layers. The Theca Interna layer cells differenciate into steroidogenic cells produce the Androgen Androsteinedione in response to the Gonadotrophin Luteinising hormone (LH).
• Theca Cell layer becomes vascularised.
• Granulosa cells become responsive to Follicle Stimulating Hormone (FSH) and start producing 17β-Oestrodiol and small amounts of Inhibin and Progesterone.

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Dominant Follicle

Histological Section of the Ovary showing Characteristics of the Dominant Graafian Follicle - Courtesy of J.Bredl, Copyright RVC 2008

• Only a single Dominant follicle forms with each wave of folliculogenesis.
• The follicles Antrum enlarges due to the Granulosa cells becoming receptive to LH.
• All of the other follicles undergo degeneration.
• Ovulation of the Dominant follicles Oocyte occurs in response to an LH surge.

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Atretic Follicles

Histological Section of the Ovary showing Characteristics of the Atretic Follicle - Courtesy of J.Bredl, Copyright RVC 2008

• Atresia is the the fate of most of the ovarian follicles as only a small number are ovulated.
• It may occur at any stage of follicular development from primary to tertiary follicle.
• Atretic follicles are characterized by:
  • Numerous pyknotic nuclei in the granulosa, absence of mitosis in this layer.
  • Disruption of the basal lamina.
  • Presence of free floating cells with dark staining, pyknotic nuclei in the antral cavity.
  • Presence of clear vacuoles in the oocyte, disruption of the oolemma.

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Function

• Follicular cells produce hormones important for the progression of the oestrus cycle. Theca cells produce Androstienedione which is converted to 17β-Oestrodiol (E2) by the Granulosa cell enzyme Aromatase. At low levels E2 acts to negatively feedback to the hypothalamus and pituitary gland, inhibiting production of Gonadotrophin releasing Hormone (GnRH) and LH + FSH respectively. When the E2 level increases above the level of threshold it acts to stimulate gonadotrophin release. This results in the LH surge responsible for Ovulation.
• The positive feedback action of E2 leading to a surge in LH only and not FSH is due to the selective action of Inhibin. Inhibin is a hormone produced by granulosa cells that selectively inhibits FSH production by the pituitary gland.