The Follicle, Steroidogenesis And Corpus Luteum

Question 1

Follicle translates

Answer 1

to ‘little bag’ in Latin.

Question 2

It functions as both

Answer 2

an endocrine gland and the site of oogenesis.

Question 3

The follicle is composed of the following three cell types:

Answer 3

1. Thecal cells
2. Granulosa cells
3. Oocyte

Question 4

Theca is the Latin word for ‘casing’ ‘outer covering’, or ‘sheath’. Thecal cells of the ovarian follicle form

Answer 4

an envelope of connective tissue surrounding the granulosa cells.

Question 5

There are two thecal cell populations

Answer 5

the theca interna and the theca externa

Question 6

The theca interna and the theca externa are believed to have originated from

Answer 6

mesenchymal cells and fibroblast-like precursor cells of the fetal ovary, respectively.

Question 7

The theca interna contains the thecal endocrine cells. The theca interna is

Answer 7

highly vascularized and
the cells are highly differentiated steroid-secreting cells with numerous mitochondria, abundant endoplasmic reticulum and lipid vesicles.

Question 8

The theca externa is a fibrous connective tissue layer of

Answer 8

loosely organized non-steriodogenic cells that lies between the theca interna and the interfollicular stroma.

Question 9

The first thecal cells differentiate into the theca interna when follicle development has reached

Answer 9

the early secondary stage with the appearance of the second layer of cuboidal granulosa cells

Question 10

Current evidence suggests that substances produced by the follicle GC stimulate

Answer 10

Thecal cell differentiation

Question 11

Thecal cell differentiation is

Answer 11

gonadotropin-independent.

Question 12

The thecal cells become responsive to the gonadotropin luteinizing hormone (LH) of LH receptors (LHR) around this time and

Answer 12

steroidogenic enzymes are activated

Question 13

Thecal cells express LHR

Answer 13

throughout folliculogenesis.

Question 14

The thecal layer is essential for

Answer 14

maintaining the structural integrity of the follicle

Question 15

The thecal layer is composed of extracellular matrix factors such as

Answer 15

collagen, vimentin, laminin, fibronectin, and proteoglycans.

Question 16

The thecal layer undergoes dynamic changes and remodeling during

Answer 16

folliculogenesis that are critical for both development and ovulation.

Question 17

The thecal layers however do not undergo the

Answer 17

continuous massive proliferation shown by granulosa cells.

Question 18

The vascularized theca interna also delivers nutrients to the

Answer 18

avascular GC Cumulus cells and oocyte.

Question 19

Androgens are produced by the thecal cells in small follicles and regulate the expression of

Answer 19

follicle stimulating hormone receptors (FSHR) by GC as well as exerting paracrine functions within the ovary and diffusing into granulosa cells for conversion into estrogens.

Question 20

Granulosa cells: Are believed to originate from

Answer 20

the ovarian surface epithelium.

Question 21

After follicle activation the single layer of columnar granulosa cells begins

Answer 21

to proliferate exponentially resulting in many cell layers as well as differentiation into sub-populations with different phenotypes (mural, antral, cumulus) in the fully mature follicle.

Question 22

The different GC phenotypes are likely determined by their

Answer 22

location in the follicle (proximity to the oocyte or thecal cells) and by the paracrine substances they produce.

Question 23

GC are the site of

Answer 23

estradiol production from thecal androgens by the actions of the enzyme aromatase (CYP19A1).

Question 24

The aromatase activity in GC of large pre-ovulatory follicles is significantly

Answer 24

greater (as much as 700 times) than in associated thecal cells.

Question 25

Steroidogenesis in GC is stimulated by

Answer 25

the gonadotropin follicle stimulating hormone (FSH).

Question 26

FSHR expression exists exclusively

Answer 26

on the surface of GCs.

Question 27

FSHR expression increases as the follicle grows stimulated by

Answer 27

rising estrogen levels.

Question 28

Each GC has approximately 1500 FSH receptors

Answer 28

by the secondary stage of follicular development.

Question 29

FSHR number per GC remains relatively constant for the remainder of development with the further increase in total FSHR number caused by

Answer 29

the increasing number of GC not the number of receptors per cell.

Question 30

Rising estradiol levels appear to increase

Answer 30

the total number of estradiol receptors (ER) on the GC.

Question 31

In the presence of estradiol, FSH stimulates the

Answer 31

formation of LH receptors on the GC.

Question 32

Multiple local factors then coordinately enhance LHR expression and follicular growth to prepare for

Answer 32

the LH surge and ovulation.

Question 33

It is essential that the follicle acquires sufficient

Answer 33

LH receptors to be able to respond appropriately to the LH surge.

Question 34

As an endocrine tissue, the follicle is an active site for

Answer 34

steroidogenesis, producing a wide spectrum of steroids (each steroid serving as a substrate for the subsequent one).

Question 35

Follicles primary steroid products are the estrogens of the menstrual cycle and involves

Answer 35

functions of both the thecal and granulosa cells.

Question 36

Steroid hormones bind to and activate receptor molecules

Answer 36

that serve as transcription factors to regulate gene expression.

Question 37

However, steroidogenic cells store very little steroid. Thus, steroidogenic response requires

Answer 37

synthesis of new steroid.

Question 38

The acute regulation of steroidogenesis is determined by

Answer 38

the action of steroidogenic acute regulatory protein (StAR).

Question 39

Steroidogenic enzymes govern steroidogenesis

Answer 39

quantitatively (how much; by regulating P450scc gene expression) as well as qualitatively (what type of steroid is produced; mediated by many enzymes and cofactors).

Question 40

Steroidogenic enzymes fall into two groups:

Answer 40

i) cytochrome P450 enzymes ii) hydroxysteroid dehydrogenases

Question 41

A cytochrome P450 may be either

Answer 41

type 1 (in mitochondria) or type 2 (in endoplasmic reticulum)

Question 42

A hydroxysteroid dehydrogenase may belong to either the

Answer 42

aldo-keto reductase or short-chain dehydrogenase/reductase families.

Question 43

The activities of these enzymes are modulated

Answer 43

by posttranslational modifications and by cofactors.

Question 44

Cholesterol is the precursor of

Answer 44

the sex steroid hormones.

Question 45

Cholesterol contains 27 carbon atoms and must undergo conversion reactions to

Answer 45

reduce the carbon atom number to 21 (C21: progestagens) 19 (C19: androgens), and finally to 18 carbon atoms (C18: estrogens).

Question 46

The first and rate-limiting step in steroidogenesis occurs in

Answer 46

the mitochondria and involves the conversion of cholesterol to pregnenolone, promoted by a single membrane-anchored P450scc enzyme CYP11A1.

Question 47

However, this enzymatically complex step is subject to multiple regulatory mechanisms resulting in the ability to

Answer 47

fine tune steroid hormone production levels.

Question 48

The hydroxylation reaction involves

Answer 48

the removal of a six-carbon unit from the side chain of cholesterol.

Question 49

It is hydroxylated (+OH) at C-20 then at C-22 and the bond

Answer 49

between these carbon atoms is subsequently cleaved by desmolase.

Question 50

Pregnenolone is converted into

Answer 50

progesterone

Question 51

The conversion of pregnenolone into progesterone occurs in two steps both catalyzed by a

Answer 51

42-kDa microsomal enzyme 3ß-hydroxy-steroid dehydrogenase-isomerase (3ßHSD)

Question 52

The synthesis of androgens starts with the

Answer 52

hydroxylation of progesterone at C-17 by the enzyme 17a-hydroxylase (CYP17A) to produce 17 hydroxy-progesterone.

Question 53

The side chain consisting of C-20 and C-21 is then cleaved by Ct7-20 lyase to yield

Answer 53

androstenedione.

Question 54

Testosterone another androgen is formed by the reduction of

Answer 54

the 17-keto group of androstenedione by 17 B hydroxy-steroid dehydrogenase (17BHSD).

Question 55

Estrogens are synthesized in the GC from androgens by

Answer 55

removal of the C-19 angular methyl group and formation of an aromatic A ring catalyzed by aromatase (CYP19A1)

Question 56

Estrone is the most abundant estrogen and can be formed from

Answer 56

estradiol although its main precursor is androstenedione.

Question 57

Estradiol is formed from

Answer 57

testosterone and it's the most biologically active estrogen.

Question 58

Estriol is the least biologically active of the estrogens and is formed from

Answer 58

both estrone and estradiol.

Question 59

The theca and GC have a cooperative relationship in

Answer 59

the production of estrogen.

Question 60

The thecal layer contains the enzymes to

Answer 60

produce androgens and very little estrogen.

Question 61

These androgens then diffuse into the granulosa cells where they are converted into

Answer 61

estrogens.

Question 62

This cooperative relationship is referred to as the

Answer 62

"two cell theory'.

Question 63

Corpus luteum translates to yellow body' in Latin and it is considered the

Answer 63

second major structure of the ovary although it is actually a structure that develops from the follicle.

Question 64

The process of conversion from follicle to CL is called

Answer 64

luteinization.

Question 65

Just prior to the LH surge and ovulation the follicle undergoes a series of intercellular changes that

Answer 65

completely alter its structure and physiology.

Question 66

The GC begin to undergo hypertrophy and

Answer 66

numerous lipid vacuoles start to form within their cytoplasm.

Question 67

At the time of the LH surge the follicle

Answer 67

rapidly accumulates more lipid vacuoles and the yellow pigment lutein.

Question 68

Luteinized GC (granulosa-lutein) of the ovulated follicle undergo terminal differentiation to give rise to

Answer 68

the large luteal cell population of the CL and are centrally located within the CL structure.

Question 69

The LH surge also modifies the steroidogenic capacity of the

Answer 69

GC, from an estrogen-producing cell to a progesterone- and estrogen-producing cell.

Question 70

The granulosa-lutein cells retain the

Answer 70

capacity to synthesize estrogens from androgen precursors produced by theca-lutein cells.

Question 71

Theca-lutein cells are morphologically different from

Answer 71

the granulosa-lutein cells, they are smaller, and remain at the outer edge of the CL structure.

Question 72

Theca-lutein cells maintain the ability to produce androgens and have

Answer 72

receptors for luteinizing hormone / human chorionic gonadotropin (LHCGR)

Question 73

Theca-łutein cells are more abundant than the granulosa-lutein cells

Answer 73

but the granulosa-lutein cells are more biologically active.

Question 74

Human luteal cells interact in an

Answer 74

auto- and paracrine-manner using a variety of substances including prostaglandins steroids and peptides.

Question 75

CL regulation

Answer 75

is species specific.

Question 76

Non-steroidogenic cells account for

Answer 76

70%-85% of CL cell population and participate in its physiology.

Question 77

Non-steroidogenic cells include the following:

Answer 77

1. Resident leukocytes 2. Endothelial cells (vascular cells) 3. Fibroblasts (connective tissue)

Question 78

Resident leukocytes are a rich source of

Answer 78

cytokines (interleukin 1ß (|L1fB) and tumor necrosis factor a (TNFa).

Question 79

Resident leukocytes also secrete

Answer 79

Angiogenic growth factors, prostaglandins, cytolytic enzymes (involved in the process of luteolysis) and steroid that modulate CL function.

Question 80

Endothelial cells (vascular cells) make up 50% of the mature CL cell population and

Answer 80

contribute vasoactive compounds that modulate CL activity.