Preface

This important book explores one of the most common pathologic abnormalities of the female genital tract: fibroids. A fibroid is a benign tumor originating from the smooth muscle of the uterus.

Written by authors and researchers in the field, this book examines uterine fibroids over four sections. The first section covers the clinical presentation of myoma. Some tumors are asymptomatic, whereas others may cause pelvic masses, abnormal vaginal bleeding, or pelvic pain. It also discusses sexual dysfunction as well as reproductive symptoms like infertility and recurrent pregnancy loss.

The second section deals with the diagnosis, which can be accomplished by conducting a clinical history and physical examination, including pelvic examination. Diagnosis can be confirmed via pelvic ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI), all of which can also be used to diagnose extra-uterine fibroids as well. This section includes a chapter about submucous myoma and hysteroscopy and how the latter can treat bleeding in uterine myxomatosis.

The third section deals with the management of uterine fibroids, including medical hormonal or non-hormonal treatment, herbal medicine, surgery (either open or endoscopic), and uterine artery embolization. It also discusses women's perspectives about their bodies after hysterectomy.

> **Hassan Abduljabbar** Department of Obstetrics and Gynecology, King Abdulaziz University, Jeddah, Saudi Arabia

**1**

Section 1

Clinical Presentation

Section 1

## Clinical Presentation

**3**

**Chapter 1**

**Abstract**

Bleeding

*Kizito Omona*

Fibroid, also called leiomyomas, is common tumor of the uterus. Usually, women of reproductive age are at risk of getting it. However, majority of these women develop fibroid (s) by the age of 50 years. This condition usually causes painful and unpleasant symptoms such as; heavy bleeding, prolonged periods, inter-menstrual bleeding, abdominal pain and cramps, anemia, pelvic pain and pain during sexual intercourse, among others. Abnormal bleeding, such as bleeding that occurs with fibroids and heavy periods, often lasts more than 10 days per month. This fibroid symptom involves persistent bleeding between cycles, which can severely impact one's quality of life. Abnormal bleeding, especially in fibroids, can be taken as missing three or more periods in a woman who had been having regular monthly period, or periods that last less than 21 days or more than 35 days apart from each other. Another indication of an abnormal period is bleeding

through multiple pads and tampons in a short amount of time.

menstrual bleeding, menstrual cycle

average duration of 28 days for most women.

55 years of a normal adult female [1].

**1. Introduction**

**Keywords:** per vaginal bleeding, abnormal bleeding, normal bleeding,

of oocyte, thus preparing the uterus for any possible pregnancy [1].

In a normal adult human – female, menstrual cycle occurs to provide for release

Thus, menstruation is a woman's normal monthly per vaginal bleeding, usually called "monthly period." When a woman menstruates, her body discards the monthly build-up of the lining of the uterus. The resultant blood, also called menstrual blood, and uterine tissues flow from the uterus through the cervix and then into the vagina and eventually out of the body [2]. In other words, menstruation is the cyclic and orderly sloughing off of the uterine lining which occurs in response to the interactions of hormones produced by the hypothalamus, pituitary and ovaries [3].

Menstrual cycle is, thus, divided into three phases. These are follicular or proliferative phase, ovulation and luteal or secretory phase. The number of days between the first day of menstrual bleeding of a woman's cycle to the onset of menses of the next cycle is referred to as 'the length of a menstrual cycle'. The average duration of a menstrual cycle is usually 28 days. However, some women may have shorter cycle of 21 days. Such women are referred to as 'polymenorrheic women'. Some women also have longer cycle of 35 days or more. These are called oligomenorrheic women [3]. Thus, the complete cycle may last anywhere from 21 days to 35 days with an

Menstruation begins at puberty, usually between ranging 10 to 16 years of age of a normal girl child. It ends at menopause, corresponding to average age of 45 to

## **Chapter 1** Bleeding

*Kizito Omona*

### **Abstract**

Fibroid, also called leiomyomas, is common tumor of the uterus. Usually, women of reproductive age are at risk of getting it. However, majority of these women develop fibroid (s) by the age of 50 years. This condition usually causes painful and unpleasant symptoms such as; heavy bleeding, prolonged periods, inter-menstrual bleeding, abdominal pain and cramps, anemia, pelvic pain and pain during sexual intercourse, among others. Abnormal bleeding, such as bleeding that occurs with fibroids and heavy periods, often lasts more than 10 days per month. This fibroid symptom involves persistent bleeding between cycles, which can severely impact one's quality of life. Abnormal bleeding, especially in fibroids, can be taken as missing three or more periods in a woman who had been having regular monthly period, or periods that last less than 21 days or more than 35 days apart from each other. Another indication of an abnormal period is bleeding through multiple pads and tampons in a short amount of time.

**Keywords:** per vaginal bleeding, abnormal bleeding, normal bleeding, menstrual bleeding, menstrual cycle

### **1. Introduction**

In a normal adult human – female, menstrual cycle occurs to provide for release of oocyte, thus preparing the uterus for any possible pregnancy [1].

Thus, menstruation is a woman's normal monthly per vaginal bleeding, usually called "monthly period." When a woman menstruates, her body discards the monthly build-up of the lining of the uterus. The resultant blood, also called menstrual blood, and uterine tissues flow from the uterus through the cervix and then into the vagina and eventually out of the body [2]. In other words, menstruation is the cyclic and orderly sloughing off of the uterine lining which occurs in response to the interactions of hormones produced by the hypothalamus, pituitary and ovaries [3].

Menstrual cycle is, thus, divided into three phases. These are follicular or proliferative phase, ovulation and luteal or secretory phase. The number of days between the first day of menstrual bleeding of a woman's cycle to the onset of menses of the next cycle is referred to as 'the length of a menstrual cycle'. The average duration of a menstrual cycle is usually 28 days. However, some women may have shorter cycle of 21 days. Such women are referred to as 'polymenorrheic women'. Some women also have longer cycle of 35 days or more. These are called oligomenorrheic women [3]. Thus, the complete cycle may last anywhere from 21 days to 35 days with an average duration of 28 days for most women.

Menstruation begins at puberty, usually between ranging 10 to 16 years of age of a normal girl child. It ends at menopause, corresponding to average age of 45 to 55 years of a normal adult female [1].

Ordinarily, the typical volume of blood lost during menstruation is approximately 30 milliliters (mL). Any amount of blood lost during menstruation which is greater than 80 mL is considered abnormal [4].

#### **2. Physiology of normal uterine bleeding**

There are four major circulating hormones involved in the menstrual cycle. These hormones are; follicle stimulating hormones (FSH), luteinizing hormones (LH), estradiol (estrogen) and progesterone. The concentrations of these hormones in blood vary and their levels provide characteristic changes during the menstrual cycle [5]. In particular, the body makes three main types of estrogen; estrone (E1), estradiol (E2) and estriol (E3). E1 is the only estrogen the body makes after menopause. E2 is the most common type in women of childbearing age whereas E3 is the main estrogen during pregnancy [6].

The menstrual cycle is triggered by the gonadotropin-releasing hormone (GnRH) pulse generator in the hypothalamus. The GnRH pulse generator then releases gonadotropin-releasing hormone (GnRH) [7]. This GnRH in turn stimulates the synthesis and release of the gonadotropins, luteinizing hormones (LH) and follicle stimulating hormones (FSH), from the anterior pituitary gland [5]. LH and FSH exert their effects in the ovaries. There are two types of cells responsible for hormone production within the ovarian follicle; theca cells and granulosa cells. LH acts on theca cells to produce progesterone and androstenedione. The enzyme involved is cholesterol desmolase. Upon secretion of androstenedione, the hormone diffuses to granulosa cells. FSH then stimulates the granulosa cells to convert androstenedione to testosterone and eventually 17-beta-estradiol. The enzyme involved is aromatase. The levels of 17-beta-estradiol or progesterone increases accordingly, depending on the phase of the menstrual cycle. This increase triggers a negative feedback back to the anterior pituitary to lower the levels of FSH and LH which are being produced and subsequently, the levels of 17-beta-estradiol and progesterone produced. The only exception occurs during ovulation, in which case, once a critical amount of 17-beta-estradiol is produced it provides positive feedback to the anterior pituitary instead of a negative feedback [5, 6]. This positive feedback results in increased amounts of FSH and LH, hence the LH surge bringing about ovulation [1].

The onset of the menstrual cycle, or menarche, usually at 10–16 years, begins at puberty and ceases at menopause, usually 45–55 years. The cycle has 3 phases: follicular or proliferative phase, ovulation and luteal or secretory phase [1, 5].

**Follicular Phase:** Usually, the first phase of the menstrual cycle is the follicular or proliferative phase. The phase is characterized by menstruation, resulting from shedding off of the initially thickened endometrial lining following failed fertilization or implantation. It occurs from day zero to day 14 of the menstrual cycle (see **Figures 1** and **2**), based on the average duration of 28 days cycle. There is usually variability in the length of menstrual cycle and this is due to variations in the length of the follicular phase. The main hormone during this phase is estrogen, in particular 17-beta-estradiol [1, 5] from the ovary coupled with follicle stimulating hormone (FSH), released from anterior pituitary gland. Upon release from anterior pituitary, FSH and LH slowly rise in levels and cause the growth of follicles on the surface of the ovary. This process prepares the egg for ovulation. As the follicles grow, they begin releasing estrogens and a low level of progesterone. These ovarian hormones then inhibit further release of GnRH from the hypothalamus, in a

**5**

**Figure 2.** *Menstrual flow.*

to the anterior pituitary.

negative feedback process (See **Figure 3**). Thus, as the follicular phase progresses to the end, the increased amounts of 17-beta-estradiol will provide negative feedback

Due to the rise of FSH during the first days of the menstrual cycle or follicular phase, several ovarian follicles are stimulated. These ovarian follicles compete with each other for dominance. The follicle that reaches maturity is called a Graafian

*Bleeding*

**Figure 1.**

*Hormonal changes in the menstrual cycle.*

*DOI: http://dx.doi.org/10.5772/intechopen.94079*

*Fibroids*

Ordinarily, the typical volume of blood lost during menstruation is approximately 30 milliliters (mL). Any amount of blood lost during menstruation which is

There are four major circulating hormones involved in the menstrual cycle. These hormones are; follicle stimulating hormones (FSH), luteinizing hormones (LH), estradiol (estrogen) and progesterone. The concentrations of these hormones in blood vary and their levels provide characteristic changes during the menstrual cycle [5]. In particular, the body makes three main types of estrogen; estrone (E1), estradiol (E2) and estriol (E3). E1 is the only estrogen the body makes after menopause. E2 is the most common type in women of childbearing age whereas E3 is the

The menstrual cycle is triggered by the gonadotropin-releasing hormone (GnRH) pulse generator in the hypothalamus. The GnRH pulse generator then releases gonadotropin-releasing hormone (GnRH) [7]. This GnRH in turn stimulates the synthesis and release of the gonadotropins, luteinizing hormones (LH) and follicle stimulating hormones (FSH), from the anterior pituitary gland [5]. LH and FSH exert their effects in the ovaries. There are two types of cells responsible for hormone production within the ovarian follicle; theca cells and granulosa cells. LH acts on theca cells to produce progesterone and androstenedione. The enzyme involved is cholesterol desmolase. Upon secretion of androstenedione, the hormone diffuses to granulosa cells. FSH then stimulates the granulosa cells to convert androstenedione to testosterone and eventually 17-beta-estradiol. The enzyme involved is aromatase. The levels of 17-beta-estradiol or progesterone increases accordingly, depending on the phase of the menstrual cycle. This increase triggers a negative feedback back to the anterior pituitary to lower the levels of FSH and LH which are being produced and subsequently, the levels of 17-beta-estradiol and progesterone produced. The only exception occurs during ovulation, in which case, once a critical amount of 17-beta-estradiol is produced it provides positive feedback to the anterior pituitary instead of a negative feedback [5, 6]. This positive feedback results in increased amounts of FSH and LH, hence

The onset of the menstrual cycle, or menarche, usually at 10–16 years, begins at puberty and ceases at menopause, usually 45–55 years. The cycle has 3 phases: follicular or proliferative phase, ovulation and luteal or secretory phase [1, 5].

**Follicular Phase:** Usually, the first phase of the menstrual cycle is the follicular or proliferative phase. The phase is characterized by menstruation, resulting from shedding off of the initially thickened endometrial lining following failed fertilization or implantation. It occurs from day zero to day 14 of the menstrual cycle (see **Figures 1** and **2**), based on the average duration of 28 days cycle. There is usually variability in the length of menstrual cycle and this is due to variations in the length of the follicular phase. The main hormone during this phase is estrogen, in particular 17-beta-estradiol [1, 5] from the ovary coupled with follicle stimulating hormone (FSH), released from anterior pituitary gland. Upon release from anterior pituitary, FSH and LH slowly rise in levels and cause the growth of follicles on the surface of the ovary. This process prepares the egg for ovulation. As the follicles grow, they begin releasing estrogens and a low level of progesterone. These ovarian hormones then inhibit further release of GnRH from the hypothalamus, in a

greater than 80 mL is considered abnormal [4].

**2. Physiology of normal uterine bleeding**

main estrogen during pregnancy [6].

the LH surge bringing about ovulation [1].

**4**

**Figure 1.** *Hormonal changes in the menstrual cycle.*

**Figure 2.** *Menstrual flow.*

negative feedback process (See **Figure 3**). Thus, as the follicular phase progresses to the end, the increased amounts of 17-beta-estradiol will provide negative feedback to the anterior pituitary.

Due to the rise of FSH during the first days of the menstrual cycle or follicular phase, several ovarian follicles are stimulated. These ovarian follicles compete with each other for dominance. The follicle that reaches maturity is called a Graafian

follicle. During follicular phase, estrogen suppresses production of luteinizing hormone (LH) from the pituitary gland (**Figures 4** and **5**) [5]**.**

**Ovulation phase:** Ovulation phase comes next. Ovulation occurs 14 days later after the first day of menstruation [1]. This means that with an average 28-day cycle, ovulation occurs on day 14 (see **Figure 1**).

At the end of the proliferative phase, 17-beta-estradiol (E2) levels are high due to the follicle maturation. During the follicular phase, estrogen suppresses production of luteinizing hormone (LH) from the pituitary gland but in this phase it stimulates

#### **Figure 3.** *The follicular phase [5].*

**7**

See **Figure 2**.

*Bleeding*

**Figure 5.**

*The luteal phase [5].*

*DOI: http://dx.doi.org/10.5772/intechopen.94079*

estradiol fall at the end of ovulation [1, 5, 6].

maturation a follicle and thickens the endometrial lining. At this time, only 17-betaestradiol (E2) provides positive feedback for FSH and LH production. A critical level of 17-beta-estradiol must be reached, at least 200 picograms per milliliter of plasma, to cause this positive feedback. The high levels of FSH and LH present during this time is called the LH surge [5]. The release of LH matures the ovum much further and weakens the wall of the follicle in the ovary, thus causing the fully developed follicle to release its secondary oocyte, in a process known as ovulation. After being released from the ovary, the ovum, also called egg, is swept into the fallopian tube. The changes to the cervix which was initiated during the follicular phase is even further increased in ovulation phase allowing for increased, waterier cervical mucus in order to better accommodate the possible sperm. The levels of 17-beta-

**Luteal or Secretory phase:** The luteal phase follows ovulation. It is characterized by the development of corpus luteum, secretion of progesterone and the formation of thick mucus which blocks the cervix. Blocking of the cervix is in anticipation that implantation has occurred [5]. Luteal phase always occurs from day 14 to day 28 of the cycle (See **Figure 1**). Progesterone stimulated by LH is the dominant hormone during this phase to prepare the corpus luteum and the endometrium for possible implantation of the fertilized ovum. As the luteal phase comes to an end, progesterone will provide negative feedback to the anterior pituitary to decrease FSH and LH levels and subsequently, the 17-beta-estradiol (E2) and progesterone levels [1, 5, 6]. Therefore, at the end of luteal phase, in the absence of implantation (pregnancy), when the level of progesterone drops, menses or menstruation occurs [1].

**3. Clinical significance of physiology of normal uterine bleeding**

A normal woman has an average of 450 menses throughout her lifetime. It is therefore, very important to fully understand the menstrual cycle and its physiology

**Figure 4.** *The ovulation phase [5].*

*Fibroids*

follicle. During follicular phase, estrogen suppresses production of luteinizing

**Ovulation phase:** Ovulation phase comes next. Ovulation occurs 14 days later after the first day of menstruation [1]. This means that with an average

At the end of the proliferative phase, 17-beta-estradiol (E2) levels are high due to the follicle maturation. During the follicular phase, estrogen suppresses production of luteinizing hormone (LH) from the pituitary gland but in this phase it stimulates

hormone (LH) from the pituitary gland (**Figures 4** and **5**) [5]**.**

28-day cycle, ovulation occurs on day 14 (see **Figure 1**).

**6**

**Figure 4.**

*The ovulation phase [5].*

**Figure 3.**

*The follicular phase [5].*

**Figure 5.** *The luteal phase [5].*

maturation a follicle and thickens the endometrial lining. At this time, only 17-betaestradiol (E2) provides positive feedback for FSH and LH production. A critical level of 17-beta-estradiol must be reached, at least 200 picograms per milliliter of plasma, to cause this positive feedback. The high levels of FSH and LH present during this time is called the LH surge [5]. The release of LH matures the ovum much further and weakens the wall of the follicle in the ovary, thus causing the fully developed follicle to release its secondary oocyte, in a process known as ovulation. After being released from the ovary, the ovum, also called egg, is swept into the fallopian tube.

The changes to the cervix which was initiated during the follicular phase is even further increased in ovulation phase allowing for increased, waterier cervical mucus in order to better accommodate the possible sperm. The levels of 17-betaestradiol fall at the end of ovulation [1, 5, 6].

**Luteal or Secretory phase:** The luteal phase follows ovulation. It is characterized by the development of corpus luteum, secretion of progesterone and the formation of thick mucus which blocks the cervix. Blocking of the cervix is in anticipation that implantation has occurred [5]. Luteal phase always occurs from day 14 to day 28 of the cycle (See **Figure 1**). Progesterone stimulated by LH is the dominant hormone during this phase to prepare the corpus luteum and the endometrium for possible implantation of the fertilized ovum. As the luteal phase comes to an end, progesterone will provide negative feedback to the anterior pituitary to decrease FSH and LH levels and subsequently, the 17-beta-estradiol (E2) and progesterone levels [1, 5, 6].

Therefore, at the end of luteal phase, in the absence of implantation (pregnancy), when the level of progesterone drops, menses or menstruation occurs [1]. See **Figure 2**.

#### **3. Clinical significance of physiology of normal uterine bleeding**

A normal woman has an average of 450 menses throughout her lifetime. It is therefore, very important to fully understand the menstrual cycle and its physiology as various complications may occur later in life for a woman [8]. The knowledge of this forms the cornerstone of making appropriate diagnosis and investigation [9].

Menstruation begins at puberty, usually between 10 to 16 years of age of a normal girl child. It ends at menopause, corresponding to average age of 45 to 55 years of a normal adult female [1].

Ordinarily, the typical volume of blood lost during menstruation is approximately 30 milliliters (mL). Any amount of blood lost during menstruation which is greater than 80 mL is considered abnormal [4].

The clinician needs to know all these in order to make appropriate diagnosis and investigation. Anything sort of this could result in gross errors.

#### **4. Bleeding in fibroids**

Fibroids are growths of muscle and fibrous tissue in or on the wall of the uterus. They range in size from seedlings which are undetectable by human eye, to bulky masses that can disfigure or enlarge the uterus. One can have a single fibroid or multiple fibroids (See **Figure 6**) [10].

#### **4.1 Normal versus abnormal bleeding**

It is usually very difficult to tell between what is normal and what is abnormal when it comes to menstruation. This is because of the huge variation in women to the point that what is normal for one might be abnormal for another. Heavy menstrual flow is highly subjective.

In addition to the above, there are many factors that influence length, heaviness, and frequency of a woman's menstrual flow. Thus, paying close attention to one's monthly period and observing the trend becomes paramount to detecting whether or not one has abnormal or normal menstrual flow. This observance might need to have been done over a significant period of time [11].

Vaginal bleeding is considered to be abnormal if it occurs between a woman's menstrual cycles, in situations where flow is significantly heavier than normal for a particular individual or when it occurs after menopause.

#### *4.1.1 Normal bleeding*

Bleeding in normal period typically lasts between 3 and 8 days, usually with a heavier menstrual flow for the first two days. The flow gets increasingly lighter as

**9**

*Bleeding*

*DOI: http://dx.doi.org/10.5772/intechopen.94079*

*4.1.2 Abnormal periods or fibroids bleeding*

in a short amount of time [10, 11].

are associated with menstrual cramps.

leads to heavier periods [11].

1.Use of birth control pills

See **Figure 6.**

that can severely affect one's quality of life [11].

**4.2 The cause of heavy bleeding in fibroids**

the number of days progress. Women with normal periods may have limited spot-

On another hand, abnormal bleeding, such as those bleedings occurring in fibroids and in heavy periods, usually lasts more than 10 days per month. Fibroid symptom involves persistent bleeding between menstrual cycles. This is to the point

Abnormal bleeding can be considered missing 3 or more periods in a row, or periods which occur less than 21 days or more than 35 days apart from each other. Another sign of an abnormal period is bleeding through multiple pads and tampons

The cause of heavy bleeding in fibroid is not well understood. Since fibroids are connected to your uterine lining, the fibroids can exert pressure against the uterine wall and cause the endometrial tissue to bleed more than normal [11].

During menstrual period, the uterine lining sheds off and the uterus has two basic mechanisms to stop itself from bleeding. The first mechanism is through the normal blood-clotting working throughout the body by forming plugs within the blood vessels. Secondly, since the uterus is a muscle, it also has the ability to contract the bleeding vessels of the uterus, thus stopping the bleeding. The contractions

However, it is believed that fibroids interfere with adequate and proper contraction of the uterus. In this way, it does not stop menstrual bleeding adequately. Additionally, fibroids produce growth factors (proteins) that stimulate relaxation of the uterine blood vessels and thus causing more blood in the uterine cavity, which

The treatment of abnormal bleeding depend on; the cause, patient age, severity

2.Hormone injections or a hormone-releasing IUD (intra-uterine device)

endometrial polyp removal, myomectomy or even hysterectomy

bleeding and cause necrosis of the fibroids, especially larger fibroids [13].

3.Surgery to control bleeding or to remove growths, such as fibroids, that are causing the bleeding. Surgical options available include endometrial ablation,

The two medical treatments for heavy menstrual bleeding have been effective enough. First, levonorgestrel intra-uterine system was FDA approved for the treatment of heavy menstrual bleeding in 2009. It is highly effective for decreasing menstrual bleeding, treating anemia and improving the overall quality of life. Secondly, tranexamic acid, also FDA approved for heavy menstrual bleeding in 2009, reduces menstrual blood loss in 40% of women and improves quality of life. Moreover, in women with fibroids, tranexamic acid has been shown to decrease heavy menstrual

**4.3 Treatment of abnormal bleeding and fibroids bleeding**

of bleeding and whether one wants to have children or not [12]. Otherwise, the common medical treatment options are;

ting, cramps that ache and bloating that goes away once the period is over.

**Figure 6.** *Different locations of fibroids [10].*

*Fibroids*

of a normal adult female [1].

**4. Bleeding in fibroids**

greater than 80 mL is considered abnormal [4].

or multiple fibroids (See **Figure 6**) [10].

**4.1 Normal versus abnormal bleeding**

have been done over a significant period of time [11].

particular individual or when it occurs after menopause.

strual flow is highly subjective.

*4.1.1 Normal bleeding*

investigation. Anything sort of this could result in gross errors.

as various complications may occur later in life for a woman [8]. The knowledge of this forms the cornerstone of making appropriate diagnosis and investigation [9]. Menstruation begins at puberty, usually between 10 to 16 years of age of a normal girl child. It ends at menopause, corresponding to average age of 45 to 55 years

Ordinarily, the typical volume of blood lost during menstruation is approximately 30 milliliters (mL). Any amount of blood lost during menstruation which is

The clinician needs to know all these in order to make appropriate diagnosis and

Fibroids are growths of muscle and fibrous tissue in or on the wall of the uterus. They range in size from seedlings which are undetectable by human eye, to bulky masses that can disfigure or enlarge the uterus. One can have a single fibroid

It is usually very difficult to tell between what is normal and what is abnormal when it comes to menstruation. This is because of the huge variation in women to the point that what is normal for one might be abnormal for another. Heavy men-

In addition to the above, there are many factors that influence length, heaviness, and frequency of a woman's menstrual flow. Thus, paying close attention to one's monthly period and observing the trend becomes paramount to detecting whether or not one has abnormal or normal menstrual flow. This observance might need to

Vaginal bleeding is considered to be abnormal if it occurs between a woman's menstrual cycles, in situations where flow is significantly heavier than normal for a

Bleeding in normal period typically lasts between 3 and 8 days, usually with a heavier menstrual flow for the first two days. The flow gets increasingly lighter as

**8**

**Figure 6.**

*Different locations of fibroids [10].*

the number of days progress. Women with normal periods may have limited spotting, cramps that ache and bloating that goes away once the period is over.

#### *4.1.2 Abnormal periods or fibroids bleeding*

On another hand, abnormal bleeding, such as those bleedings occurring in fibroids and in heavy periods, usually lasts more than 10 days per month. Fibroid symptom involves persistent bleeding between menstrual cycles. This is to the point that can severely affect one's quality of life [11].

Abnormal bleeding can be considered missing 3 or more periods in a row, or periods which occur less than 21 days or more than 35 days apart from each other. Another sign of an abnormal period is bleeding through multiple pads and tampons in a short amount of time [10, 11].

#### **4.2 The cause of heavy bleeding in fibroids**

The cause of heavy bleeding in fibroid is not well understood. Since fibroids are connected to your uterine lining, the fibroids can exert pressure against the uterine wall and cause the endometrial tissue to bleed more than normal [11]. See **Figure 6.**

During menstrual period, the uterine lining sheds off and the uterus has two basic mechanisms to stop itself from bleeding. The first mechanism is through the normal blood-clotting working throughout the body by forming plugs within the blood vessels. Secondly, since the uterus is a muscle, it also has the ability to contract the bleeding vessels of the uterus, thus stopping the bleeding. The contractions are associated with menstrual cramps.

However, it is believed that fibroids interfere with adequate and proper contraction of the uterus. In this way, it does not stop menstrual bleeding adequately. Additionally, fibroids produce growth factors (proteins) that stimulate relaxation of the uterine blood vessels and thus causing more blood in the uterine cavity, which leads to heavier periods [11].

#### **4.3 Treatment of abnormal bleeding and fibroids bleeding**

The treatment of abnormal bleeding depend on; the cause, patient age, severity of bleeding and whether one wants to have children or not [12].

Otherwise, the common medical treatment options are;


The two medical treatments for heavy menstrual bleeding have been effective enough. First, levonorgestrel intra-uterine system was FDA approved for the treatment of heavy menstrual bleeding in 2009. It is highly effective for decreasing menstrual bleeding, treating anemia and improving the overall quality of life. Secondly, tranexamic acid, also FDA approved for heavy menstrual bleeding in 2009, reduces menstrual blood loss in 40% of women and improves quality of life. Moreover, in women with fibroids, tranexamic acid has been shown to decrease heavy menstrual bleeding and cause necrosis of the fibroids, especially larger fibroids [13].

#### **5. Conclusion**

Research on bleeding in fibroids is still far from over. Much more is still wanting. Uterine fibroids are common debilitating problems for many women. Almost 60% of women with fibroids report that symptoms affect their quality of life and impede their physical activity. Again, 24% of them report that fibroid symptoms prevent them from reaching their full potential at work. Heavy menstrual bleeding, which is the most common symptom of uterine fibroids, affects approximately 1.4 million women per year.

#### **Acknowledgements**

I do acknowledge the technical guidance of my colleagues in the Faculty of Health Sciences of Uganda Martyrs' University. In a special way I appreciate Ms. Scovia Mbabazi, the former Associate Dean and Mr. Mathias Lwenge, the current Associate Dean at the faculty.

### **Conflict of interest**

The author declares no conflict of interest.

#### **Author details**

Kizito Omona Uganda Martyrs University, Faculty of Health Sciences, Kampala, Uganda

\*Address all correspondence to: komona@umu.ac.ug

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**11**

*Bleeding*

**References**

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*DOI: http://dx.doi.org/10.5772/intechopen.94079*

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2020. https://www.hormone.org/ your-health-and-hormones/glandsand-hormones-a-to-z/hormones/

[7] Ferin, M. *The Hypothalamic-Hypophyseal-Ovarian Axis and the Menstrual Cycle.* New York : Global Library of Women's Medicine, 2008.

[9] Gunn, H. M., et al. Menstrual Patterns in the First Gynecological Year: A Systematic Review. *J Pediatr Adolesc Gynecol.* 2018. Vol. 31, 6, pp. 557-565.

[8] Alvergne, A. and Jun, Högqvist, T. V. Is Female Health Cyclical? Evolutionary Perspectives on Menstruation. *Trends Ecol. Evol. (Amst.).* 2018. Vol. 33, 6, pp.

1966. Vol. 45, 3, pp. 320-351.

### **References**

*Fibroids*

**5. Conclusion**

1.4 million women per year.

Associate Dean at the faculty.

The author declares no conflict of interest.

**Acknowledgements**

**Conflict of interest**

**10**

**Author details**

Uganda Martyrs University, Faculty of Health Sciences, Kampala, Uganda

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Research on bleeding in fibroids is still far from over. Much more is still wanting. Uterine fibroids are common debilitating problems for many women. Almost 60% of women with fibroids report that symptoms affect their quality of life and impede their physical activity. Again, 24% of them report that fibroid symptoms prevent them from reaching their full potential at work. Heavy menstrual bleeding, which is the most common symptom of uterine fibroids, affects approximately

I do acknowledge the technical guidance of my colleagues in the Faculty of Health Sciences of Uganda Martyrs' University. In a special way I appreciate Ms. Scovia Mbabazi, the former Associate Dean and Mr. Mathias Lwenge, the current

\*Address all correspondence to: komona@umu.ac.ug

provided the original work is properly cited.

Kizito Omona

[1] Thiyagarajan, D. K., Basit, H. and Jeanmonod, R. Physiology, *Menstrual Cycle.* Treasure Island(FL) : StatPearls Publishing, 2020.

[2] Office on Women's Health [OWH]. What is Menstruation? *Womenshealth. gov.* [Online] 2018. https://www. womenshealth.gov/menstrual-cycle/ your-menstrual-cycle.

[3] Reed, B. G. and Carr, B. R. *The Normal Menstrual Cycle and the Control of Ovulation.* Texas : Endotext, 2018. NBK279054.

[4] Hallberg, L., et al. Menstrual blood loss--a population study. Variation at different ages and attempts to define normality. *Acta Obstet Gynecol Scand.* 1966. Vol. 45, 3, pp. 320-351.

[5] Anon. Hormonal Control of Human Reproduction. [book auth.] C. Molnar and J. Gair. *Concept of Biology- 1st Canadian Edition.* Ottawa : BCcampus, 2019.

[6] Hormone Health Network. Hormone Health Network."Estrogen | Hormone Health Network" . *Hormone.org.* [Online] 2020. https://www.hormone.org/ your-health-and-hormones/glandsand-hormones-a-to-z/hormones/ estrogen.

[7] Ferin, M. *The Hypothalamic-Hypophyseal-Ovarian Axis and the Menstrual Cycle.* New York : Global Library of Women's Medicine, 2008.

[8] Alvergne, A. and Jun, Högqvist, T. V. Is Female Health Cyclical? Evolutionary Perspectives on Menstruation. *Trends Ecol. Evol. (Amst.).* 2018. Vol. 33, 6, pp. 399-414.

[9] Gunn, H. M., et al. Menstrual Patterns in the First Gynecological Year: A Systematic Review. *J Pediatr Adolesc Gynecol.* 2018. Vol. 31, 6, pp. 557-565.

[10] Azura Vascular Care. Could I Be Bleeding Due to Fibroids? *azuravascularcare.com.* [Online] 2018. https://www.azuravascularcare.com/ infoufe/bleeding-due-to-fibroids/.

[11] USA Fibroids Centre. DO FIBROIDS CAUSE HEAVY BLEEDING? *usafibroidcentre.com.* [Online] 2020. https://www.usafibroidcenters.com/ blog/fibroids-cause-heavy-menstrualbleeding/.

[12] Anon. Uterine Fibroids & Abnormal Bleeding. *umwomenshealth.org.* [Online] n.d. https://www.umwomenshealth. org/conditions-treatments/ uterine-fibroids-abnormal-bleeding.

[13] Laughlin-Tommaso, S. K. and Clinic, Mayo. Treatment of Heavy Menstrual Bleeding in Women With Uterine Fibroids. *ClinicalTrials.gov.* [Online] 2020. https://clinicaltrials.gov/ct2/ show/NCT03317795.

**13**

cells [3].

place [5].

**Chapter 2**

**Abstract**

**1. Introduction**

Inflammation and Ovulation

The ovulation is a complex physiological process which is very commonly affected in patients with PCOS. Understanding inflammatory process involved in ovulation is important with respect to its onset, diagnosis and treatment. There are multiple inflammatory factors are associated with ovulation however anovulation and contraception have not been therapeutically explored in context with inflammatory process. Therefore, this chapter is written to help readers to understand the basics of inflammation in ovulation and role of inflammatory mediators in ovulation. This chapter also describes genetic and molecular aspects linked to ovulation.

**Keywords:** inflammation, ovulation, cytokine, prostaglandin, TNF-alpha, PPAR-γ

Mammalian ovulation is a fundamental physiological process involves the rupturing of follicle and releasing of the dominant follicle from the ovary into the fallopian tube where it has the potential to get fertilized if it exposed to sperm. Oocyte is covered up of four different layers namely the granulosa cells, which form a protected layer within oocyte and the extra follicular microenvironment, then theca layers of theca-interna and theca-externa, tunica albuginea and the outermost one is epithelium [1, 2]. A thin transparent layer between oocyte and follicular membrane is made up of secretions by the oocyte, termed as zona pellucida [2]. The developing oocyte enclosed in a ovarian follicle which is float in a dynamic fluid i.e. Follicular fluid (FF), contain variety of signaling molecules such as polysaccharides, hormones, cytokines, chemokines, growth factors, reactive oxygen species (ROS), metabolites, antioxidant enzymes, etc. The follicular fluid formed in developing antral follicles, primarily to support the development and protection of oocytes. These molecules are also acts as communicators between somatic and germ

The duration of ovulatory process in humans, pigs, rats and rabbits takes approximately 40, 22, 12 and 10 hours respectively to complete. Substantial tissue remodeling occurs during the ovulation, the follicle increases its own size, and the layers of theca cells fuse with the tunica albuginea, resulting into thinner and permitting rupturing of follicle to release the oocyte [4]. The mature oocyte when released by the rupturing of follicle its uptake facilitated by the fingure like opening projections of fallopian tube which is known as fimbriae, if fertilization occur here then the blastocyst further transfer it towards the uterus where the pregnancy takes

Inflammation is defensive mechanism of the cells that is crucial to health and it is delineated as a local immune response of living vascularized tissues to endogenous and exogenous stimuli and its actions is to removal of injurious stimuli with

*Pankaj Pant and Havagiray R. Chitme*

## **Chapter 2** Inflammation and Ovulation

*Pankaj Pant and Havagiray R. Chitme*

#### **Abstract**

The ovulation is a complex physiological process which is very commonly affected in patients with PCOS. Understanding inflammatory process involved in ovulation is important with respect to its onset, diagnosis and treatment. There are multiple inflammatory factors are associated with ovulation however anovulation and contraception have not been therapeutically explored in context with inflammatory process. Therefore, this chapter is written to help readers to understand the basics of inflammation in ovulation and role of inflammatory mediators in ovulation. This chapter also describes genetic and molecular aspects linked to ovulation.

**Keywords:** inflammation, ovulation, cytokine, prostaglandin, TNF-alpha, PPAR-γ

#### **1. Introduction**

Mammalian ovulation is a fundamental physiological process involves the rupturing of follicle and releasing of the dominant follicle from the ovary into the fallopian tube where it has the potential to get fertilized if it exposed to sperm. Oocyte is covered up of four different layers namely the granulosa cells, which form a protected layer within oocyte and the extra follicular microenvironment, then theca layers of theca-interna and theca-externa, tunica albuginea and the outermost one is epithelium [1, 2]. A thin transparent layer between oocyte and follicular membrane is made up of secretions by the oocyte, termed as zona pellucida [2].

The developing oocyte enclosed in a ovarian follicle which is float in a dynamic fluid i.e. Follicular fluid (FF), contain variety of signaling molecules such as polysaccharides, hormones, cytokines, chemokines, growth factors, reactive oxygen species (ROS), metabolites, antioxidant enzymes, etc. The follicular fluid formed in developing antral follicles, primarily to support the development and protection of oocytes. These molecules are also acts as communicators between somatic and germ cells [3].

The duration of ovulatory process in humans, pigs, rats and rabbits takes approximately 40, 22, 12 and 10 hours respectively to complete. Substantial tissue remodeling occurs during the ovulation, the follicle increases its own size, and the layers of theca cells fuse with the tunica albuginea, resulting into thinner and permitting rupturing of follicle to release the oocyte [4]. The mature oocyte when released by the rupturing of follicle its uptake facilitated by the fingure like opening projections of fallopian tube which is known as fimbriae, if fertilization occur here then the blastocyst further transfer it towards the uterus where the pregnancy takes place [5].

Inflammation is defensive mechanism of the cells that is crucial to health and it is delineated as a local immune response of living vascularized tissues to endogenous and exogenous stimuli and its actions is to removal of injurious stimuli with starting the healing process [6]. Inflammation is also initiated when the cells die from deficiency of nutrients or hypoxia, a condition that often is originated by the blood flow loss to the site. The chemical mediators of the inflammation generally originate from the blood plasma, platelets, white blood cells (monocytes, neutrophils, basophils, and macrophages), endothelial cells lining of the blood vessels, mast cells, and injured tissue cells. The chemical mediators responsible for the inflammation is histamine, that stimulates vasodilation and increases the vascular permeability, and lysosomal substances acting as vascular permeability enhancer which are secreted from neutrophils, and certain small proteins in the complement system, namely C3a and C5a. Various cytokines released by inflammatory cells also have vasoactive and chemotactic function. Many cells produce prostaglandins which linked to the fever and pain of inflammation; a group of fatty acids which involves in the augmentation of vascular permeability of the other substances, platelets aggregation; which is essential for coagulation [6].

The objective of this review is to understand and establish a relationship between how the inflammation as well as different mediators of inflammation that influence the ovulation process that is crucial for clinical management and prediction of gynecological complications for future study.

#### **2. Inflammatory genetic mechanism**

Inflammation is detected throughout many normal reproductive progressions, for the duration of ovulation, menstruation, implantation, as well as parturition. Ovulatory cycle is also considered as inflammatory process because the rupturing of dominant follicle undergoes the process of healing [7]. Throughout ovulation, the role of inflammation is very significant in terms of folliculogenesis and luteinization. In the course of the rupturing of follicle, there is significant surge of intra-follicular pressure which leads to weakening of follicle layer by the stimulation of gonadotropins resulted in inflammation [8]. The inflammation notably persuades in both ovulation and tissue remodeling phase which resulted in events of hyperemia, vasodilation, edema, collagenolysis, and proliferation of cells [1].

Wissing et al. isolated differentially expressed 1186 genes in human granulosa cells (GC) before and 36 h after the administration of hCG, besides 572 genes found to be up-regulated which represented angiogenesis, inflammation, extracellular matrix and growth factors and 614 genes down-regulated which denoted cell cycle and about 72 genes which has been earlier establish linked with ovarian cancer. H19/mir675, CD24, CLDN11, ANKRD22, and FBXO32 adds as new ovulation related genes and PTGS2, an inflammatory gene heavily up-regulated [5].

#### **3. Inflammatory oxygen species and ovulation**

The release of mature oocyte relies on the expansion of cumulus oocyte complex (COC), where the reactive oxygen species (ROS) function as critical modulator of inflammatory reaction. Residual growing follicles promoted to apoptosis by the ROS [8]. Simultaneously estrogen synthesis started with the influx of catalase and Glutathione (GSH) i.e. a non-enzymatic antioxidant species exists in oocytes and embryos, in growing residual follicles for the maintenance of normal ovarian function and counter the apoptotic process. The luteal phase begins with progesterone production for the maintenance of preliminary stage of pregnancy, if fertilization did not occur then degeneration of corpus luteum starts [2]. For the

**15**

*Inflammation and Ovulation*

cells transformation [11].

**4. PCOS and inflammation**

*DOI: http://dx.doi.org/10.5772/intechopen.94107*

induction of cell proliferation, maturation, cellular-differentiation and ovulation the physiological level of ROS is very important [9]. Augmented ROS may outcomes to DNA damage, activation of signaling cascades, and epigenetic alterations [10]. Inflammation in the course of ovulation is also responsible for the oxidative stress, damaging of DNA and moreover in the neoplastic ovarian surface epithelium (OSE)

Elevated level of inflammation also involves in the pathogenicity of many reproductive disorder such as polycystic ovary syndrome (PCOS), characterized by biochemical hyperandrogenemia, chronic anovulation, and polycystic ovaries. About 5 to 15% of reproductive age woman are suffering with this disorder in the world. It is anticipated that the metabolic disorders associated with PCOS and the pathogenesis of PCOS due to systemic inflammation as well as dysfunctioning of mitochondria. About 33% adolescent PCOS girls are more prone to metabolic disorder are obese, which is 3 to 5 folds higher if compared with same age healthy girls and body mass index (BMI) [9]. Studies reported and found the significant increased level of monocytes, lymphocytes, CRP, interleukins IL-1, IL-6, IL-18, pro-inflammatory cytokines and TNF- α in addition to increased production of advanced oxidation protein, protein carbonylation and lipid peroxidation in PCOS patients compared with same reproductive aged healthy persons [9]. The PCOS patients suffered with chronic inflammation [12, 13]. Along with the deficiency of antioxidant i.e. Vitamin C, Vitamin E and Superoxide dismutases (SOD), this leads to cause inflammatory milieu and risk to develop the obesity, type-1 diabetes,

insulin resistance, hyperandrogenism, and cardiovascular ailment [1, 14].

The surge of luteinizing hormone (LH) stimulate the production of cyclic adenosine monophosphate (cAMP), steroidal hormones, histamine discharge and various mediators of inflammation e.g. prostaglandins, bradykinins, C-reactive protein (CRP), Proinflammatory cytokines, etc. [1]. Christina et al. study states that the successful folliculogenesis, oocyte maturation, and ovulation require a healthy

There are many findings illustrate that the importance of untroubled inflammatory response for proper folliculogenesis and ovulation, if it altered, may contribute to oocyte quality concern and reproductive dysfunctions such as anovulation, infertility, menstrual irregularities, etc. [5, 8]. It is reported that low dose of Aspirin taken by the patients suffering with higher systemic inflammation

The level of LH also positive correlation with release of prostaglandins and eicosanoids that are the source to trigger the fibroblasts, promotes the angiogenesis and hyperemia, collagenase activation, release of proteolytic enzymes, some of which degrade the follicular connective tissue resulting ovulation, and cause the inflammation. The gene hyaluronan (HA) synthase-2 (Has2) associated with COC matrix formation. Bradykinin play a key role in vasodilation which appears to be 10

**5. Anti-inflammatory agents and ovulation**

were able to reestablish the pregnancy [4, 12].

**6. Correlation between hormone and inflammation**

inflammatory response.

#### *Inflammation and Ovulation DOI: http://dx.doi.org/10.5772/intechopen.94107*

*Fibroids*

starting the healing process [6]. Inflammation is also initiated when the cells die from deficiency of nutrients or hypoxia, a condition that often is originated by the blood flow loss to the site. The chemical mediators of the inflammation generally originate from the blood plasma, platelets, white blood cells (monocytes, neutrophils, basophils, and macrophages), endothelial cells lining of the blood vessels, mast cells, and injured tissue cells. The chemical mediators responsible for the inflammation is histamine, that stimulates vasodilation and increases the vascular permeability, and lysosomal substances acting as vascular permeability enhancer which are secreted from neutrophils, and certain small proteins in the complement system, namely C3a and C5a. Various cytokines released by inflammatory cells also have vasoactive and chemotactic function. Many cells produce prostaglandins which linked to the fever and pain of inflammation; a group of fatty acids which involves in the augmentation of vascular permeability of the other substances,

The objective of this review is to understand and establish a relationship between how the inflammation as well as different mediators of inflammation that influence the ovulation process that is crucial for clinical management and

Inflammation is detected throughout many normal reproductive progressions,

Wissing et al. isolated differentially expressed 1186 genes in human granulosa cells (GC) before and 36 h after the administration of hCG, besides 572 genes found to be up-regulated which represented angiogenesis, inflammation, extracellular matrix and growth factors and 614 genes down-regulated which denoted cell cycle and about 72 genes which has been earlier establish linked with ovarian cancer. H19/mir675, CD24, CLDN11, ANKRD22, and FBXO32 adds as new ovulation related genes and PTGS2, an inflammatory gene heavily up-regulated [5].

The release of mature oocyte relies on the expansion of cumulus oocyte complex

(COC), where the reactive oxygen species (ROS) function as critical modulator of inflammatory reaction. Residual growing follicles promoted to apoptosis by the ROS [8]. Simultaneously estrogen synthesis started with the influx of catalase and Glutathione (GSH) i.e. a non-enzymatic antioxidant species exists in oocytes and embryos, in growing residual follicles for the maintenance of normal ovarian function and counter the apoptotic process. The luteal phase begins with progesterone production for the maintenance of preliminary stage of pregnancy, if fertilization did not occur then degeneration of corpus luteum starts [2]. For the

for the duration of ovulation, menstruation, implantation, as well as parturition. Ovulatory cycle is also considered as inflammatory process because the rupturing of dominant follicle undergoes the process of healing [7]. Throughout ovulation, the role of inflammation is very significant in terms of folliculogenesis and luteinization. In the course of the rupturing of follicle, there is significant surge of intra-follicular pressure which leads to weakening of follicle layer by the stimulation of gonadotropins resulted in inflammation [8]. The inflammation notably persuades in both ovulation and tissue remodeling phase which resulted in events of hyperemia, vasodilation, edema, collagenolysis, and proliferation of

platelets aggregation; which is essential for coagulation [6].

prediction of gynecological complications for future study.

**3. Inflammatory oxygen species and ovulation**

**2. Inflammatory genetic mechanism**

**14**

cells [1].

induction of cell proliferation, maturation, cellular-differentiation and ovulation the physiological level of ROS is very important [9]. Augmented ROS may outcomes to DNA damage, activation of signaling cascades, and epigenetic alterations [10]. Inflammation in the course of ovulation is also responsible for the oxidative stress, damaging of DNA and moreover in the neoplastic ovarian surface epithelium (OSE) cells transformation [11].

#### **4. PCOS and inflammation**

Elevated level of inflammation also involves in the pathogenicity of many reproductive disorder such as polycystic ovary syndrome (PCOS), characterized by biochemical hyperandrogenemia, chronic anovulation, and polycystic ovaries. About 5 to 15% of reproductive age woman are suffering with this disorder in the world. It is anticipated that the metabolic disorders associated with PCOS and the pathogenesis of PCOS due to systemic inflammation as well as dysfunctioning of mitochondria. About 33% adolescent PCOS girls are more prone to metabolic disorder are obese, which is 3 to 5 folds higher if compared with same age healthy girls and body mass index (BMI) [9]. Studies reported and found the significant increased level of monocytes, lymphocytes, CRP, interleukins IL-1, IL-6, IL-18, pro-inflammatory cytokines and TNF- α in addition to increased production of advanced oxidation protein, protein carbonylation and lipid peroxidation in PCOS patients compared with same reproductive aged healthy persons [9]. The PCOS patients suffered with chronic inflammation [12, 13]. Along with the deficiency of antioxidant i.e. Vitamin C, Vitamin E and Superoxide dismutases (SOD), this leads to cause inflammatory milieu and risk to develop the obesity, type-1 diabetes, insulin resistance, hyperandrogenism, and cardiovascular ailment [1, 14].

#### **5. Anti-inflammatory agents and ovulation**

The surge of luteinizing hormone (LH) stimulate the production of cyclic adenosine monophosphate (cAMP), steroidal hormones, histamine discharge and various mediators of inflammation e.g. prostaglandins, bradykinins, C-reactive protein (CRP), Proinflammatory cytokines, etc. [1]. Christina et al. study states that the successful folliculogenesis, oocyte maturation, and ovulation require a healthy inflammatory response.

There are many findings illustrate that the importance of untroubled inflammatory response for proper folliculogenesis and ovulation, if it altered, may contribute to oocyte quality concern and reproductive dysfunctions such as anovulation, infertility, menstrual irregularities, etc. [5, 8]. It is reported that low dose of Aspirin taken by the patients suffering with higher systemic inflammation were able to reestablish the pregnancy [4, 12].

#### **6. Correlation between hormone and inflammation**

The level of LH also positive correlation with release of prostaglandins and eicosanoids that are the source to trigger the fibroblasts, promotes the angiogenesis and hyperemia, collagenase activation, release of proteolytic enzymes, some of which degrade the follicular connective tissue resulting ovulation, and cause the inflammation. The gene hyaluronan (HA) synthase-2 (Has2) associated with COC matrix formation. Bradykinin play a key role in vasodilation which appears to be 10 folds increased during ovulation. The serum C- reactive protein (CRP), a marker of inflammation also raised to stimulate the production of interlukin-6 from macrophages, tumor necrosis factor α (TNFα) and the competent system of inflammatory response further activated by the adipocytes [13].

#### **7. Role of proinflammatory cytokines**

The role of proinflammatory cytokines is also important throughout folliculogenesis and induction of ovulation [5]. Higher level of follicular TNF-α resulted in the poor quality of oocyte which compromised with the fertility, also the elevated level of interleukin (IL-6) associated with less chances of conceiving while the another interleukin (IL-1) found to be regulated by FSH and its higher follicular level has been resulted in the higher chance on embryo implantation [7, 15].

#### **8. Nucleotide leukin rich polypeptide -3 inflammasomes**

A recent finding added a new mechanism for ovulatory process regulation, suggested that the NLRP3 activation of nucleotide leukin rich polypeptide 3 (NLRP3) inflammasomes started before the ovulation lasting completion of ovulation. They induces the follicular development by 52 hours' treatment using Pregnant mare serum gonadotropin (PMSG). It was found that the expression of NLRP3 inflammasomes and adaptor protein apoptosis-associated speck-like protein (ASC) significantly increased, and it was appeared a dramatic surge in caspase-1 activity and production of IL-1β [16].

#### **9. Gonadotropin in inflammation**

Gonadotropin surge trigger the ovlation with the parllel stimulation of two gens of preovulatory follicles in granulosa cells, prostaglandin-endoperoxide synthase 2 (PTGS2) and progesterone receptor (PGR). Secretion of LH stimulates the induction of both PTGS2 and PGR in preovulatory granulosa cells. Expression of PTGS2 stimulates inflammation by releasing pro-inflammatory prostaglandins wheras anti-inflammatory action through the PGR by the supression of proinflamatory genes or thru the stimulation of antiinflammatory genes. Higher level of PGE2 and PTGS2 are associated with the ovarian disorders such as ovarian carcinoma, ovarian hyperstimulation syndrome (OHSS) as well as polycystic ovarian syndrome (PCOS) [11].

#### **10. Inflammatory prostaglandins**

Prostaglandins (PGs) are signaling molecules derived from dietary fats with clinically relevant roles in reproductive biology. PGE2, for instance, promotes ovulation downstream of the luteinizing hormone surge. Excess consumption of nonsteroidal anti-inflammatory drugs, which inhibit prostaglandin-endoperoxide synthase (cyclooxygenase or Cox), is associated with reversible female infertility, likely due to failed ovulation. On the other hand, proinflammatory cytokines increase PGF2α associated with corpus luteum development and immune cell recruitment [17].

**17**

**15. Interleukins**

*Inflammation and Ovulation*

**11. Adipokines**

**12. Omentin**

**13. Oxidative stress**

**14. Tumor necrosis factor-α**

*DOI: http://dx.doi.org/10.5772/intechopen.94107*

potential role of adiponectin in folliculogenesis.

A study (Bongrani et, al.) based on the adipokines roles in the pathophysiology of PCOS, they analyzed the adipokines profile in the normal-weight PCOS patients and obese women with PCOS and comparison of these with the women whose only have a Polycystic ovary morphology. Whereas they found the PCOS patient reported with lower adiponectin level in serum as well as FF, and also the lower expression in adipose tissue of AdipoR1 and AdipoR2. In granulosa cells AdipoR1 expression was positively correlated with the follicular numbers, oocytes count and embryos, on the other hand there was no significant difference in AdipoR2 reporters was found. No correlation was established among the FF adiponectin concentration and expression of its receptor, AdipoR1/AdipoR2 in GCs. Dysregulation of adiponectin may be likely mechanisms which could be responsible for impairment of insulin-sensitivity in PCOS patient, and it seems to be independent of insulin resistance severity and a

The concentration of Omentin in FF was found to be positively correlated with BMI, higher in obese patients compared to the normal weight patients. They also point out that the omentin may possibly be controlled by means of inflammation, because the expression of omentin altered in inflammatory conditions [18].

ROS is necessary to maintain the normal female reproductive physiology, it is involved in the oocyte maturation, corpus luteum apoptosis as well as embryonic development process. The release of mature oocyte depends on the expansion of cumulus oocyte complex (COC), where the reactive oxygen species (ROS) function as critical modulator of inflammatory reaction. The exposure of ROS may lead to undergo transformative alterations of epithelial cells in the ovary and fallopian tubes [10].

It has a significant role in the process of ovulation as well as to excrete out the damaged corpous luteum from the ovarian tissue. It works by the ligand gated

receptors, TNFR-I and TNFR-II [10, 19]. It is also linked with the various pathological conditions when its level elevated. It is also reported that the infertile women with PCOS reported to have higher free fatty acids and blood serum level of TNF-α when compared with the healthy patients. Oxidative stressed cells also found to release higher levels of TNF-α than the normal ovarian epithelial cells which results in an autocrine surge of TNF-α mRNA as well as in the form of expression in other pro-

Interleukin-15 is an important interleukin which is negatively associated with

the oocyte maturation. It belongs to the cytokines family having four α-helix

inflammatory cytokines, chemokines, and angiogenic factors [10, 20, 21].

### **11. Adipokines**

*Fibroids*

folds increased during ovulation. The serum C- reactive protein (CRP), a marker of inflammation also raised to stimulate the production of interlukin-6 from macrophages, tumor necrosis factor α (TNFα) and the competent system of inflammatory

The role of proinflammatory cytokines is also important throughout folliculogenesis and induction of ovulation [5]. Higher level of follicular TNF-α resulted in the poor quality of oocyte which compromised with the fertility, also the elevated level of interleukin (IL-6) associated with less chances of conceiving while the another interleukin (IL-1) found to be regulated by FSH and its higher follicular level has been resulted in the higher chance on embryo implantation [7, 15].

A recent finding added a new mechanism for ovulatory process regulation, suggested that the NLRP3 activation of nucleotide leukin rich polypeptide 3 (NLRP3) inflammasomes started before the ovulation lasting completion of ovulation. They induces the follicular development by 52 hours' treatment using Pregnant mare serum gonadotropin (PMSG). It was found that the expression of NLRP3 inflammasomes and adaptor protein apoptosis-associated speck-like protein (ASC) significantly increased, and it was appeared a dramatic surge in

Gonadotropin surge trigger the ovlation with the parllel stimulation of two gens of preovulatory follicles in granulosa cells, prostaglandin-endoperoxide synthase 2 (PTGS2) and progesterone receptor (PGR). Secretion of LH stimulates the induction of both PTGS2 and PGR in preovulatory granulosa cells. Expression of PTGS2 stimulates inflammation by releasing pro-inflammatory prostaglandins wheras anti-inflammatory action through the PGR by the supression of proinflamatory genes or thru the stimulation of antiinflammatory genes. Higher level of PGE2 and PTGS2 are associated with the ovarian disorders such as ovarian carcinoma, ovarian hyperstimulation syndrome (OHSS) as well as polycystic ovar-

Prostaglandins (PGs) are signaling molecules derived from dietary fats with clinically relevant roles in reproductive biology. PGE2, for instance, promotes ovulation downstream of the luteinizing hormone surge. Excess consumption of nonsteroidal anti-inflammatory drugs, which inhibit prostaglandin-endoperoxide synthase (cyclooxygenase or Cox), is associated with reversible female infertility, likely due to failed ovulation. On the other hand, proinflammatory cytokines increase PGF2α associated with corpus luteum development and immune cell

**8. Nucleotide leukin rich polypeptide -3 inflammasomes**

response further activated by the adipocytes [13].

caspase-1 activity and production of IL-1β [16].

**9. Gonadotropin in inflammation**

ian syndrome (PCOS) [11].

**10. Inflammatory prostaglandins**

**7. Role of proinflammatory cytokines**

**16**

recruitment [17].

A study (Bongrani et, al.) based on the adipokines roles in the pathophysiology of PCOS, they analyzed the adipokines profile in the normal-weight PCOS patients and obese women with PCOS and comparison of these with the women whose only have a Polycystic ovary morphology. Whereas they found the PCOS patient reported with lower adiponectin level in serum as well as FF, and also the lower expression in adipose tissue of AdipoR1 and AdipoR2. In granulosa cells AdipoR1 expression was positively correlated with the follicular numbers, oocytes count and embryos, on the other hand there was no significant difference in AdipoR2 reporters was found. No correlation was established among the FF adiponectin concentration and expression of its receptor, AdipoR1/AdipoR2 in GCs. Dysregulation of adiponectin may be likely mechanisms which could be responsible for impairment of insulin-sensitivity in PCOS patient, and it seems to be independent of insulin resistance severity and a potential role of adiponectin in folliculogenesis.

#### **12. Omentin**

The concentration of Omentin in FF was found to be positively correlated with BMI, higher in obese patients compared to the normal weight patients. They also point out that the omentin may possibly be controlled by means of inflammation, because the expression of omentin altered in inflammatory conditions [18].

#### **13. Oxidative stress**

ROS is necessary to maintain the normal female reproductive physiology, it is involved in the oocyte maturation, corpus luteum apoptosis as well as embryonic development process. The release of mature oocyte depends on the expansion of cumulus oocyte complex (COC), where the reactive oxygen species (ROS) function as critical modulator of inflammatory reaction. The exposure of ROS may lead to undergo transformative alterations of epithelial cells in the ovary and fallopian tubes [10].

#### **14. Tumor necrosis factor-α**

It has a significant role in the process of ovulation as well as to excrete out the damaged corpous luteum from the ovarian tissue. It works by the ligand gated receptors, TNFR-I and TNFR-II [10, 19]. It is also linked with the various pathological conditions when its level elevated. It is also reported that the infertile women with PCOS reported to have higher free fatty acids and blood serum level of TNF-α when compared with the healthy patients. Oxidative stressed cells also found to release higher levels of TNF-α than the normal ovarian epithelial cells which results in an autocrine surge of TNF-α mRNA as well as in the form of expression in other proinflammatory cytokines, chemokines, and angiogenic factors [10, 20, 21].

#### **15. Interleukins**

Interleukin-15 is an important interleukin which is negatively associated with the oocyte maturation. It belongs to the cytokines family having four α-helix

bundle, i.e. pleiotropic glycoprotein. It was reported to be higher in women with an unsuccessful assisted reproductive techniques outcomes (median value 1.4 pg./ml) than of the women those succeeded the clinical pregnancy (median value 0.8 pg./ml) [22]. The IL-6 is a regulator of cumulus cell-oocyte complex (COC) expansion and responsible for the quality of murine oocyte during the in-vitro fertilization.

#### **16. Matrix metalloproteinases**

The another factor which has been found to be involved in follicular development as well as in the ovulation process are Matrix metalloproteinases (MMPs). The matrix metalloproteinases activities regulated by the specific tissue inhibitors called metalloproteinases (TIMPs) and endogenous inhibitors. The balance of both these is very essential for their activity and to maintain the normal ovarian physiology. It is well noticed that the MMP-2 and MMP-9 level increased during and before the 3 hours of ovulation if compared to 20–22 hour before the ovulation. Augmented level of MMP-9 also postulated in the PCOS pathophysiology and is also linked with progression and etiological to many other ailments such as cystic fibrosis, asthma, ulcerative colitis, cardiovascular disorders, atherosclerosis, etc. [23, 24].

#### **17. Peroxisome proliferator-activated receptor gamma**

The Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) is established to have an ability to prevent the expression of various signaling molecules also regulates the levels of prostaglandins through regulation of cyclooxygenase-2 and differentiation of immune cells especially those which are a part of inflammation. Thereby controls ovarian function, fertilization, and ovulation. Its proinflammatory activity is linked to the formation of prostaglandin E by downregulation of COX-2 mRNA of granulosa cells whereas it is upregulated twice in PCOS [25]. It is also being proven that the PPAR-γ controls genes responsible for expression of TNFalpha and Interleukins along with others. The study is supported by use of PPAR-γ agonist which affected the functioning of ovaries by involving signal transduction of insulin and IGF [20].

#### **18. Chemokines**

Earlier study reported the expression of chemokine receptor-2 (C-C motif) (CCR2) in the human ovarian cumulus-oocyte complexes, theca cells, preovulatory follicles and in feline ovarian follicle walls. This receptor is believed to be involved in folliculogenesis and determines the reproductive lifespan of female [25] (**Figure 1**).

#### **19. Conclusions**

Inflammation is believed to be involved in triggering the process of ovulation. There are several factors, genes, receptors, proinflammatory mediators playing important but diverse role in ovulation. The extent of their role and intensity of reaction induced by them required to be studied to understand their clinical applicability.

**19**

**Acknowledgements**

*Inflammatory process in ovulation.*

**Figure 1.**

**Conflict of interest**

We acknowledge the financial help received from Grant4Target.

The authors declare no conflict of interest.

*Inflammation and Ovulation*

*DOI: http://dx.doi.org/10.5772/intechopen.94107*

*Fibroids*

**16. Matrix metalloproteinases**

disorders, atherosclerosis, etc. [23, 24].

of insulin and IGF [20].

**18. Chemokines**

**19. Conclusions**

applicability.

**17. Peroxisome proliferator-activated receptor gamma**

bundle, i.e. pleiotropic glycoprotein. It was reported to be higher in women with an unsuccessful assisted reproductive techniques outcomes (median value 1.4 pg./ml) than of the women those succeeded the clinical pregnancy (median value 0.8 pg./ml) [22]. The IL-6 is a regulator of cumulus cell-oocyte complex (COC) expansion and responsible for the quality of murine oocyte during the in-vitro fertilization.

The another factor which has been found to be involved in follicular development as well as in the ovulation process are Matrix metalloproteinases (MMPs).

The Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) is established

to have an ability to prevent the expression of various signaling molecules also regulates the levels of prostaglandins through regulation of cyclooxygenase-2 and differentiation of immune cells especially those which are a part of inflammation. Thereby controls ovarian function, fertilization, and ovulation. Its proinflammatory activity is linked to the formation of prostaglandin E by downregulation of COX-2 mRNA of granulosa cells whereas it is upregulated twice in PCOS [25]. It is also being proven that the PPAR-γ controls genes responsible for expression of TNFalpha and Interleukins along with others. The study is supported by use of PPAR-γ agonist which affected the functioning of ovaries by involving signal transduction

Earlier study reported the expression of chemokine receptor-2 (C-C motif) (CCR2) in the human ovarian cumulus-oocyte complexes, theca cells, preovulatory follicles and in feline ovarian follicle walls. This receptor is believed to be involved in folliculogenesis and determines the reproductive lifespan of female [25] (**Figure 1**).

Inflammation is believed to be involved in triggering the process of ovulation. There are several factors, genes, receptors, proinflammatory mediators playing important but diverse role in ovulation. The extent of their role and intensity of reaction induced by them required to be studied to understand their clinical

The matrix metalloproteinases activities regulated by the specific tissue inhibitors called metalloproteinases (TIMPs) and endogenous inhibitors. The balance of both these is very essential for their activity and to maintain the normal ovarian physiology. It is well noticed that the MMP-2 and MMP-9 level increased during and before the 3 hours of ovulation if compared to 20–22 hour before the ovulation. Augmented level of MMP-9 also postulated in the PCOS pathophysiology and is also linked with progression and etiological to many other ailments such as cystic fibrosis, asthma, ulcerative colitis, cardiovascular

**18**

#### **Figure 1.**

*Inflammatory process in ovulation.*

#### **Acknowledgements**

We acknowledge the financial help received from Grant4Target.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Fibroids*

#### **Author details**

Pankaj Pant and Havagiray R. Chitme\* Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, India

\*Address all correspondence to: hrchitme@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**21**

*Inflammation and Ovulation*

**References**

2019; 6(4), 103.

*DOI: http://dx.doi.org/10.5772/intechopen.94107*

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[10] Savant, S. S., Sriramkumar, S., & O'Hagan, H. M.. The role of inflammation and inflammatory mediators in the development, progression, metastasis, and

[11] Park, C. J., Lin, P. C., Zhou, S., Barakat, R., Bashir, S. T., Choi, J. M., ... & Ko, C. J.. Progesterone Receptor Serves the Ovary as a Trigger of Ovulation and a Terminator of Inflammation. Cell reports. 2020;31(2):

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[13] Shaaban, Z., Khoradmehr, A., Amiri-Yekta, A., Shirazi, M. R. J., & Tamadon, A.. Pathophysiologic mechanisms of obesity-and chronic inflammation-related genes in etiology of polycystic ovary syndrome. Iranian Journal of Basic Medical Sciences.

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#### **References**

*Fibroids*

**20**

**Author details**

Pankaj Pant and Havagiray R. Chitme\*

provided the original work is properly cited.

Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, India

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: hrchitme@gmail.com

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[2] Mancini, V., & Pensabene, V. . Organs-On-Chip Models of the Female Reproductive System. Bioengineering. 2019; 6(4), 103.

[3] Souček, K., Malenovská, A., Kahounová, Z., Remšík, J., Holubcová, Z., Soukup, T., & Hampl, A.. Presence of growth/differentiation factor-15 cytokine in human follicular fluid, granulosa cells, and oocytes. Journal of assisted reproduction and genetics. 2018; 35(8), 1407-1417.

[4] Espey, L. L.. Comprehensive analysis of ovarian gene expression during ovulation using differential display. In Differential Display Methods and Protocols. Humana Press. 2006;219-241.

[5] Wissing, M. L., Kristensen, S. G., Andersen, C. Y., Mikkelsen, A. L., Høst, T., Borup, R., & Grøndahl, M. L.. Identification of new ovulationrelated genes in humans by comparing the transcriptome of granulosa cells before and after ovulation triggering in the same controlled ovarian stimulation cycle. Human reproduction. 2014;29(5):997-1010.

[6] Agita, A., & Alsagaff, M. T.. Inflammation, immunity, and hypertension. Acta Med Indones. 2017;49(2):158-165.

[7] Papler, T. B., Bokal, E. V., Maver, A., Kopitar, A. N., & Lovrečić, L.. Transcriptomic analysis and meta-analysis of human granulosa and cumulus cells. PloS one. 2015;10(8):e0136473.

[8] Adams, J., Liu, Z., Ren, Y. A., Wun, W. S., Zhou, W., Kenigsberg, S., & Richards, J.. Enhanced inflammatory

transcriptome in the granulosa cells of women with polycystic ovarian syndrome. The Journal of Clinical Endocrinology & Metabolism. 2016;101(9):3459-3468.

[9] Khashchenko, E., Vysokikh, M., Uvarova, E., Krechetova, L., Vtorushina, V., Ivanets, T., & Sukhikh, G.. Activation of Systemic Inflammation and Oxidative Stress in Adolescent Girls with Polycystic Ovary Syndrome in Combination with Metabolic Disorders and Excessive Body Weight. Journal of Clinical Medicine. 2020;9(5):1399.

[10] Savant, S. S., Sriramkumar, S., & O'Hagan, H. M.. The role of inflammation and inflammatory mediators in the development, progression, metastasis, and chemoresistance of epithelial ovarian cancer. Cancers. 2018;10(8):251.

[11] Park, C. J., Lin, P. C., Zhou, S., Barakat, R., Bashir, S. T., Choi, J. M., ... & Ko, C. J.. Progesterone Receptor Serves the Ovary as a Trigger of Ovulation and a Terminator of Inflammation. Cell reports. 2020;31(2): 107496.

[12] Radin, R. G., Sjaarda, L. A., Silver, R. M., Nobles, C. J., Mumford, S. L., Perkins, N. J., & Schisterman, E. F.. C-Reactive protein in relation to fecundability and anovulation among eumenorrheic women. Fertility and sterility. 2018;109(2):232-239.

[13] Shaaban, Z., Khoradmehr, A., Amiri-Yekta, A., Shirazi, M. R. J., & Tamadon, A.. Pathophysiologic mechanisms of obesity-and chronic inflammation-related genes in etiology of polycystic ovary syndrome. Iranian Journal of Basic Medical Sciences. 2019;22(12):1378.

[14] Wang, S., He, G., Chen, M., Zuo, T., Xu, W., & Liu, X.. The

role of antioxidant enzymes in the ovaries. Oxidative medicine and cellular longevity. 2017;2017. DOI: 10.1155/2017/4371714

[15] Da Broi, M. G., Giorgi, V. S. I., Wang, F., Keefe, D. L., Albertini, D., & Navarro, P. A.. Influence of follicular fluid and cumulus cells on oocyte quality: clinical implications. Journal of assisted reproduction and genetics. 2018;35(5):735-751.

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[18] Bongrani, A., Mellouk, N., Rame, C., Cornuau, M., Guérif, F., Froment, P., & Dupont, J.. Ovarian Expression of Adipokines in Polycystic Ovary Syndrome: A Role for Chemerin, Omentin, and Apelin in Follicular Growth Arrest and Ovulatory Dysfunction?. International journal of molecular sciences. 2019;20(15):3778.

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[20] Lee, J. Y., Tae, J. C., Kim, C. H., Hwang, D., Kim, K. C., Suh, C. S., & Kim, S. H.. Expression of the genes for peroxisome proliferator-activated receptor-γ, cyclooxygenase-2, and proinflammatory cytokines in granulosa cells from women with polycystic ovary

syndrome. Clinical and experimental reproductive medicine. 2017;44(3):146.

[21] Kowsar, R., Keshtegar, B., & Miyamoto, A.. Understanding the hidden relations between pro-and antiinflammatory cytokine genes in bovine oviduct epithelium using a multilayer response surface method. Scientific reports. 2019;9(1):1-17.

[22] Spanou, S., Kalogiannis, D., Zapanti, E., Gazouli, M., Sfontouris, I. A., Siristatidis, C., & Mastorakos, G.. Interleukin 15 concentrations in follicular fluid and their effect on oocyte maturation in subfertile women undergoing intracytoplasmic sperm injection. Journal of assisted reproduction and genetics. 2018;35(6):1019-1025.

[23] Daan, N. M., Koster, M. P., de Wilde, M. A., Dalmeijer, G. W., Evelein, A. M., Fauser, B. C., & de Jager, W.. Biomarker profiles in women with PCOS and PCOS offspring; a pilot study. PLoS One. 2016;11(11):e0165033.

[24] Hrabia, A., Wolak, D., Kwaśniewska, M., Kieronska, A., Socha, J. K., & Sechman, A.. Expression of gelatinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-2 and TIMP-3) in the chicken ovary in relation to follicle development and atresia. Theriogenology. 2019;125,268-276.

[25] Santos, A. G. A., Pereira, L. A. A. C., Viana, J. H. M., Russo, R. C., & Campos-Junior, P. H. A.. The CC-chemokine receptor 2 is involved in the control of ovarian folliculogenesis and fertility lifespan in mice. Journal of Reproductive Immunology. 2020;141:103174.

**23**

Section 2

Diagnosis
