1 Overview of Menstrual Cycle

Menstrual cycle starts at the age of 12 to 15 years, which marks the onset of puberty.

Commencement of menstrual cycle is called menarche.

Menstrual cycle ceases at the age of 45 to 50 years.

Permanent cessation of menstrual cycle in old age is called menopause.

Duration of Menstrual Cycle

Duration of menstrual cycle is usually 28 days.

But, under physiological conditions, it may vary between 20 and 40 days.

Changes During Menstrual Cycle

Series of changes occur in ovary and accessory sex organs during each menstrual cycle.

All the changes occur simultaneously.

Changes are divided into four groups:

1. Ovarian changes.
2. Uterine changes.
3. Vaginal changes.
4. Changes in cervix.

2 Ovarian Changes During Menstrual Cycle

Changes in ovary during menstrual cycle occur in two phases:

1. Follicular phase.
2. Luteal phase.

Follicular Phase

Follicular phase extends from 5th day of cycle until the time of ovulation, which takes place on the 14th day.

During this phase development of ovarian follicles and maturation of ovum take place.

Luteal Phase

Luteal phase extends between 15th and 28th day of menstrual cycle.

During this phase corpus luteum is developed and hence the name luteal phase.

3 Ovarian Follicles

The follicles gradually grow into a matured follicle through various stages.

Different Ovarian Follicles

1. Primordial follicle.
2. Primary follicle.
3. Vesicular follicle.
4. Matured follicle or Graafian follicle.

1. Primordial Follicle

At the time of puberty, both the ovaries contain about 3,00,000 to 4,00,000 primordial follicles.

Diameter of primordial follicle is about 15 to 20 μ and that of ovum is about 10 μ.

Each primordial follicle has an immature ovum which is incompletely surrounded by granulosa cells.

Granulosa cells provide nutrition to ovum during childhood.

Granulosa cells also secrete oocyte maturation inhibiting factor which keeps the ovum in the immature stage.

All the ova present in ovaries are formed before birth.

No new ovum is developed after birth.

During onset of puberty, under the influence of follicle stimulating hormone (FSH) and luteinizing hormone (LH), the primordial follicles start growing through various stages.

2. Primary Follicle

Primordial follicle becomes the primary follicle, when ovum is completely surrounded by granulosa cells.

During this stage the follicle and ovum inside the follicle increase in size.

Diameter of this follicle increases to 30 to 40 μ and that of ovum increases to about 20 μ.

Primary follicle is not covered by a definite connective tissue capsule.

Characteristic Changes During Development of Primary Follicles

1. Proliferation of granulosa cells and increase in size of the follicle.
2. Increase in size of ovum.
3. Onset of formation of connective tissue capsule around the follicle.

Primary follicles develop into vesicular follicles.

3. Vesicular Follicle

Under the influence of FSH, about 6 to 12 primary follicles start growing and develop into vesicular follicles.

During development of vesicular follicles, many changes take place in granulosa cells and ovum.

Around the follicle, a covering sheath called theca folliculi is formed.

Changes in Granulosa Cells

1. First, the proliferation of granulosa cells occurs.
2. A cavity called follicular cavity or antrum is formed between granulosa cells.
3. Antrum is filled with a serous fluid called the liquor folliculi.
4. Ovum is pushed to one side and it is surrounded by granulosa cells which forms the germ hill or cumulus oophorus.
5. Granulosa cells which line the antrum form membrana granulosa.
6. Cells of germ hill become columnar and form corona radiata.

Changes in Ovum

1. First, ovum increases in size and its diameter increases to 100 to 150 μ.
2. Nucleus becomes larger and vesicular.
3. Cytoplasm becomes granular.
4. Thick membrane is formed around the ovum which is called zona pellucida.
5. A narrow cleft called perivitelline space appears between ovum and zona pellucida.

Formation of Theca Folliculi

Spindle cells from the stroma of ovarian cortex are modified and form a covering sheath around the follicle.

This covering sheath is known as follicular sheath or theca folliculi.

Theca folliculi divides into two layers:

i. Theca Interna

Theca interna is the inner vascular layer with loose connective tissue and epithelial cells with lipid granules.

Epithelial cells become secretory in nature and start secreting the female sex hormones, especially estrogen, which is released into the fluid of antrum.

ii. Theca Externa

Theca externa is the outer layer of follicular capsule and consists of thickly packed fibers and spindle-shaped cells.

4. Graafian Follicle

After about the 7th day of menstrual cycle, one vesicular follicle outgrows the others and becomes the dominant follicle.

It develops further to form Graafian follicle.

Other vesicular follicles degenerate by means of apoptosis.

Graafian follicle is the matured ovarian follicle with maturing ovum.

It is named after its discoverer, the Dutch physician and anatomist Regnier de Graaf.

Changes in Graafian Follicle

1. Size of follicle increases to about 10 to 12 mm.
2. At one point, follicle encroaches upon tunica albuginea and protrudes upon the surface of ovary. This protrusion is called stigma. At the stigma, tunica albuginea becomes thin.
3. Follicular cavity becomes larger and distended with fluid.
4. Ovum attains maximum size.
5. Zona pellucida becomes thick.
6. Corona radiata becomes prominent.
7. Small spaces filled with fluid appear between the cells of germ hill outside the corona radiata. These spaces weaken the attachment of the ovum to the follicular wall.
8. Theca interna becomes prominent. Its thickness becomes double with formation of rich capillary network.
9. On the 14th day of menstrual cycle, the Graafian follicle is ready for the process of ovulation.

4 Ovulation

Ovulation occurs usually on the 14th day of menstrual cycle in a normal cycle of 28 days.

Ovum, which is released into abdominal cavity, enters the fallopian tube through fimbriated end of tube.

Usually, only one ovum is released from any one of the ovaries.

LH is responsible for ovulation.

Prior to ovulation, large amount of LH is secreted (LH surge) which causes changes in the Graafian follicle leading to ovulation.

LH Surge

Stages of Ovulation

1. Graafian follicle moves towards periphery of ovary.
2. New blood vessels are formed in ovary by actions of LH and progesterone.
3. New blood vessels protrude into the wall of the follicle. This increases the blood flow to follicle.
4. Now, prostaglandin is released from granulosa cells of the follicle.
5. It causes leakage of plasma into the follicle.
6. Just before ovulation, follicle swells and protrudes against the capsule of ovary. This protrusion is called stigma.
7. Then, progesterone activates the proteolytic enzymes present in cells of theca interna.
8. These enzymes weaken the follicular capsule and cause degeneration of stigma.
9. After about 30 minutes, fluid begins to ooze from the follicle through the stigma.
10. It decreases the size of follicle causing rupture of stigma.
11. Now, ovum is released from the follicle along with fluid and plenty of small granulosa cells into the abdominal cavity.

Tests for Ovulation Time

1. Ovulation Predictor Test

This test is used to determine LH excretion in urine or increased salt content in saliva due to estrogen.

Urine test is the most common.

During LH surge prior to ovulation, large quantity of hormone is excreted in urine.

Detection of LH surge can help determine time of ovulation.

Disadvantage of this method is though the result indicates high level of LH, it does not necessarily mean that ovulation can occur.

2. Determination of Basal Body Temperature

Body temperature is measured for few days during the mid-period of menstrual cycle.

Temperature is measured in morning by placing the thermometer in rectum or vagina.

There is a slight fall in basal temperature just prior to ovulation.

The temperature increases after ovulation.

Alteration in body temperature is very mild and it is about ± 0.3 to 0.5°C.

Increase in temperature is due to the thermogenic effect of progesterone.

3. Determination of Hormonal Level in Plasma

Plasma level of FSH, LH, estrogen and progesterone are measured.

Hormone level is altered at the time of ovulation and after ovulation.

At the time of ovulation:

1. FSH level decreases.
2. LH level increases.
3. Estrogen level increases.

4. Ultrasound Scanning

Process of ovulation can be observed in ultrasound scanning.

5. Cervical Mucus Pattern

When cervical mucus spread on a slide is examined under microscope, it shows a fern pattern.

This pattern disappears after ovulation.

Significance of Determining Ovulation Time

Determination of ovulation time is helpful for family planning by rhythm method.

5 Luteal Phase

Luteal phase extends between 15th and 28th day of menstrual cycle.

During this phase corpus luteum is developed and hence the name luteal phase.

Corpus Luteum

It is also called yellow body.

Development of Corpus Luteum

Soon after the rupture of Graafian follicle and release of ovum, the follicle is filled with blood.

Now the follicle is called corpus hemorrhagicum.

Blood clots slowly and corpus hemorrhagicum is transformed into a corpus luteum.

In the corpus luteum, granulosa cells and theca interna cells are transformed into lutein cells.

Granulosa cells become granulosa lutein cells and theca interna cells become theca lutein cells.

There is accumulation of fine lipid granules and the yellow pigment granules.

The yellowish pigment granules give the characteristic yellow color to corpus luteum.

Functions of Corpus Luteum

1. Secretion of Hormones

Corpus luteum acts as a temporary endocrine gland.

It secretes large quantity of progesterone and small quantity of estrogen.

LH influences the secretion of these hormones.

2. Maintenance of Pregnancy

During pregnancy, corpus luteum maintains the pregnancy for about 3 months till placenta starts secreting estrogen and progesterone.

Abortion occurs if corpus luteum becomes inactive or removed before placenta starts secreting these hormones.

Fate of Corpus Luteum

Fate of corpus luteum depends upon whether ovum is fertilized or not.

If the Ovum is Not Fertilized

If fertilization does not take place, corpus luteum reaches maximum size about 1 week after ovulation.

During this period, it secretes large quantity of progesterone with small quantity of estrogen.

Then, it degenerates into the corpus luteum menstrualis.

Cells decrease in size and corpus luteum becomes smaller and involuted.

Afterwards, the corpus luteum menstrualis is transformed into a whitish scar called corpus albicans.

The process by which corpus luteum undergoes regression is called luteolysis.

If the Ovum is Fertilized

If ovum is fertilized and pregnancy occurs, the corpus luteum persists and increases in size.

It attains a diameter of 20 to 30 mm and is transformed into corpus luteum graviditatis (verum) or corpus luteum of pregnancy.

It remains in the ovary for 3 to 4 months.

During this period, it secretes large amount of progesterone with small quantity of estrogen, which is essential for maintenance of pregnancy.

After 3 to 4 months, placenta starts secreting these hormones and corpus luteum degenerates.

6 Uterine Changes During Menstrual Cycle

During each menstrual cycle, along with ovarian changes, uterine changes also occur simultaneously.

Uterine changes in uterus take place in three phases:

1. Menstrual phase.
2. Proliferative phase.
3. Secretory phase.

Menstrual Phase

After ovulation, if pregnancy does not occur, the thickened endometrium is shed or desquamated.

This desquamated endometrium is expelled out through vagina along with some blood and tissue fluid.

The process of shedding and exit of tissue along with blood and fluid is called menstruation or menstrual bleeding.

It lasts for about 4 to 5 days.

The period is called menstrual period or menstrual cycle.

It is also called menses, emmenia or catamenia.

The day when bleeding starts is considered as the 1st day of the menstrual cycle.

Two days before onset of bleeding, that is on 26th or 27th day of the previous cycle, there is sudden reduction in the release of estrogen and progesterone from ovary.

Decreased level of these two hormones is responsible for menstruation.

Changes in Endometrium During Menstrual Phase

1. Lack of estrogen and progesterone causes sudden involution of endometrium.
2. It leads to reduction in the thickness of endometrium, up to 65% of original thickness.
3. During the next 24 hours, the tortuous blood vessels in the endometrium undergo severe constriction.

Endometrial vasoconstriction is because of three reasons:

1. Involution of endometrium.
2. Actions of vasoconstrictor substances like prostaglandin, released from tissues of involuted endometrium.
3. Sudden lack of estrogen and progesterone, which are vasodilators.

4. Vasoconstriction leads to hypoxia, which results in necrosis of the endometrium.
5. Necrosis causes rupture of blood vessels and oozing of blood.
6. Outer layer of the necrotic endometrium is separated and passes out along with blood.
7. This process is continued for about 24 to 36 hours.
8. Within 48 hours after the reduction in secretion of estrogen and progesterone, superficial layers of endometrium are completely desquamated.
9. Desquamated tissues and the blood in the endometrial cavity initiate the contraction of uterine muscles.
10. Uterine contractions expel the blood along with desquamated uterine tissues to the exterior through vagina.

Menstrual Fluid

During normal menstruation, about 35 mL of blood along with 35 mL of serous fluid is expelled.

The blood clots as soon as it oozes into uterine cavity.

Fibrinolysin causes lysis of clot in uterine cavity itself so that, the expelled menstrual fluid does not clot.

However, in pathological conditions involving uterus, the lysis of blood clot does not occur.

So, the menstrual fluid comes out with blood clot.

Menstruation stops between 3rd and 7th day of menstrual cycle.

At the end of menstrual phase, the thickness of endometrium is only about 1 mm.

This is followed by proliferative phase.

Proliferative Phase

Proliferative phase extends usually from 5th to 14th day of menstruation, i.e., between the day when menstruation stops and the day of ovulation.

It corresponds to follicular phase of ovarian cycle.

At the end of menstrual phase, only a thin layer (1 mm) of endometrium remains as most of the endometrial stroma is desquamated.

Changes in Endometrium During Proliferative Phase

1. Endometrial cells proliferate rapidly.
2. Epithelium reappears on the surface of endometrium within the first 4 to 7 days.
3. Uterine glands start developing within the endometrial stroma.
4. Blood vessels also appear in the stroma.
5. Proliferation of endometrial cells occurs continuously so that the endometrium reaches the thickness of 3 to 4 mm at the end of proliferative phase.

All these uterine changes during proliferative phase occur because of the influence of estrogen released from ovary.

On 14th day, ovulation occurs under the influence of LH.

This is followed by secretory phase.

Secretory Phase

Secretory phase extends between 15th and 28th day of menstrual cycle, i.e., between the day of ovulation and the day when menstruation of next cycle commences.

After ovulation, corpus luteum is developed in the ovary.

It secretes a large amount of progesterone along with a small quantity of estrogen.

Estrogen causes further proliferation of cells in uterus.

Because of this, endometrium becomes very thick.

Progesterone causes further enlargement of endometrial stroma and growth of glands.

Under the influence of progesterone, endometrial glands become more tortuous and changes occur in the endometrium before commencement of secretory function.

Changes in Endometrium During Secretory Phase

1. Endometrial glands become more tortuous. Because of increase in size, the glands become more tortuous and get accommodated within the endometrium.
2. Cytoplasm of stromal cells increases because of deposition of glycogen and lipids.
3. Many new blood vessels appear within endometrial stroma. Blood vessels also become tortuous.
4. Blood supply to endometrium increases.
5. Thickness of endometrium increases up to 6 mm.

Actually, secretory phase is the preparation phase during which uterus is prepared for implantation of ovum.

At the end of secretory phase, the thickness of endometrium is 5 to 6 mm.

All the uterine changes during secretory phase occur due to the influence of estrogen and progesterone.

Estrogen is responsible for repair of damaged endometrium and growth of the glands.

Progesterone is responsible for further growth of these structures and secretory activities in the endometrium.

If a fertilized ovum is implanted during this phase and if the implanted ovum starts developing into a fetus, further changes occur in the uterus for the survival of developing fetus.

If the implanted ovum is unfertilized, if pregnancy does not occur, menstruation occurs in this phase and a new cycle begins.

7 Changes in Cervix During Menstrual Cycle

Mucous membrane of cervix also shows cyclic changes during different phases of menstrual cycle.

Proliferative Phase

Under the influence of estrogen, during proliferative phase, mucous membrane of cervix becomes thin and alkaline.

It helps in the survival and motility of sperm.

Secretory Phase

Because of actions of progesterone during secretory phase, the mucous membrane of cervix becomes thick and adhesive.

8 Changes in Vagina During Menstrual Cycle

Proliferative Phase

Epithelial cells of vagina are cornified.

Estrogen released from ovary is responsible for the cornification of vaginal epithelial cells.

Secretory Phase

Vaginal epithelium proliferates due to the actions of progesterone.

Vaginal epithelium is infiltrated with leukocytes.

These two changes increase the resistance to infection.

9 Regulation of Menstrual Cycle

The regulatory system is a highly integrated system, which includes hypothalamus, anterior pituitary and ovary with its growing follicle.

In the whole scenario, the uterus also has a vital role to play.

Hormones Involved in Regulation

Regulatory system functions through hormones of the hypothalamic-pituitary-ovarian axis.

1. Hypothalamic Hormone: GnRH

GnRH triggers the cyclic changes during menstrual cycle by stimulating secretion of FSH and LH from anterior pituitary.

GnRH secretion depends upon two factors:

1. External factors like psychosocial events, which act on hypothalamus via cortex and many other brain centers.
2. Feedback effects of ovarian changes via ovarian hormones.

2. Anterior Pituitary Hormones: FSH and LH

FSH and LH modulate ovarian and uterine changes by acting directly and/or indirectly via ovarian hormones.

FSH stimulates the recruitment and growth of immature ovarian follicles.

LH triggers ovulation and sustains corpus luteum.

Secretion of FSH and LH is under the influence of GnRH.

3. Ovarian Hormones: Estrogen and Progesterone

Estrogen and progesterone, secreted by follicle and corpus luteum, show many activities during menstrual cycle.

Ovarian follicle secretes large quantity of estrogen and corpus luteum secretes large quantity of progesterone.

Estrogen secretion reaches the peak twice in each cycle; once during follicular phase just before ovulation and another one during luteal phase.

On the other hand, estrogen is virtually absent during follicular phase till prior to ovulation.

But it plays a critical role during luteal phase.

Estrogen is responsible for the growth of follicles.

Both the steroids act together to produce the ovarian changes in uterus, cervix and vagina.

Both the ovarian hormones are under the influence of GnRH, which acts via FSH and LH.

In addition, the secretion of GnRH, FSH and LH is regulated by ovarian hormones.

Regulation of Ovarian Changes

Follicular Phase

The biological clock responsible for triggering cyclic events is the pulsatile secretion of GnRH, at about every 2 hours due to some mechanism that is not understood clearly.

Pulsatile release of GnRH stimulates secretion of FSH and LH from anterior pituitary.

FSH and LH influence growth and secretory activity of follicles.

Ovulation

LH is important for ovulation.

Without LH, ovulation does not occur even with a large quantity of FSH.

The need for excessive secretion of LH for ovulation is known as ovulatory surge for LH or luteal surge.

Luteal Phase

Ovarian changes during luteal phase depend mainly on LH.

It induces development and secretory activity of corpus luteum.

It is also necessary for the maintenance of corpus luteum.

FSH and LH stimulate the new immature follicles, resulting in the commencement of next cycle.

Regulation of Uterine Changes

Uterine changes during menstrual cycle are influenced by estrogen and progesterone.

Proliferative Phase

During proliferative stage estrogen stimulates proliferation of stromal cells in endometrium.

It also stimulates development of glands and appearance of blood vessels in the endometrial stroma.

Secretory Phase

Progesterone is responsible for endometrial changes along with estrogen during this phase.

Progesterone stimulates growth of endometrial glands and blood vessels and makes them more tortuous.

It also increases secretory activities of endometrial glands.

Thus, during the secretory phase, the blood flow and secretory functions of uterus are increased by estrogen and progesterone secreted by corpus luteum.

Menstrual Phase

If pregnancy does not occur, two days prior to menstruation, the secretion of progesterone and estrogen from corpus luteum decreases.

The secretion of FSH and LH from anterior pituitary is increased due to negative feedback.

In the absence of LH and FSH, the corpus luteum becomes inactive and starts regressing.

Sudden withdrawal (absence) of progesterone and estrogen leads to menstrual bleeding.

Lack of ovarian hormones results in release of gonadotropins once again from anterior pituitary.

It results in the onset of development of new follicles in ovary and the cycle repeats.

10 Menstrual Cycle: Phases, Hormones and Changes

11 Applied Physiology: Menstrual Disorders

1. Menstrual Symptoms

The symptoms are due to hormone withdrawal, leading to cramps in uterine muscle and withdrawal during menstruation.

Common menstrual symptoms are:

• Abdominal dysmenorrhea (menstrual pain).
• Headache.
• Irritability.
• Depression.

2. Premenstrual Syndrome

It is also called premenstrual stress syndrome, premenstrual stress or premenstrual tension.

It lasts for about 4 to 5 days prior to menstruation.

Symptoms appear due to stress and water retention caused by estrogen.

Common symptoms of this condition are:

• Emotional instability.
• Headache.
• Depression.
• Constipation.
• Abdominal cramping.
• Bloating (abdominal swelling).

3. Abnormal Menstruation

Abnormal types of menstruation are listed below.

4. Anovulatory Cycle

Menstrual bleeding occurs but the release of ovum does not occur.

It is common at puberty and few years before menopause.

When it occurs before menopause, it is called perimenopause.

If it occurs very often during childbearing years, it leads to infertility.