Menstrual Cycle and Ovulation

Introduction

The menstrual cycle is a dynamic rhythm influenced by hormonal signals and lifestyle factors. While cycle length may vary, the luteal phase is usually stable. Ovulation is marked by the luteinizing hormone surge and can be tracked by basal body temperature changes.

• A key feature of female reproduction is the cyclical release of gametes during reproductive life.
• These repeating changes are coordinated by the hypothalamic-pituitary-ovarian axis.
• In the ovary, follicles grow, mature, release the oocyte, and secrete hormones.
• In the uterus, the endometrium thickens to support implantation.
• If fertilization does not occur, the endometrium is shed as menstruation.
• These recurring ovarian and uterine events together form the menstrual cycle.
• Menstrual cycles begin at puberty.
• They temporarily stop during pregnancy and often during lactation.
• Cycles usually end permanently at menopause.
• Estrogen and progesterone regulate cyclic hormone release through feedback on the hypothalamus and pituitary gland.
• Stress, illness, nutrition, and environmental influences can alter cycle regularity.

Menstrual Cycle

• The menstrual cycle consists of regular monthly changes in the female reproductive system.
• It prepares the body for fertilization and implantation of a fertilized ovum.
• In humans and other primates, the cycle is marked externally by periodic menstruation.
• Menstruation is vaginal bleeding caused by shedding of the endometrium.
• The first menstrual period is called menarche.
• Menarche usually occurs between 12 and 14 years of age.

Duration and Phases of Menstrual Cycle

Duration of Menstrual Cycle

• The menstrual cycle averages about 28 days in many women.
• Normal cycle length usually ranges from 21 to 35 days.
• The first day of menstrual bleeding is counted as day 1 of the cycle.
• Cycle duration may vary between different women and between cycles in the same woman.
• Psychological stress, nutrition, illness, and environmental factors can influence cycle length.
• Cycles often become irregular near menopause.
• Menstruation normally stops temporarily during pregnancy and often during lactation.
• Persistent irregular cycles or abnormal bleeding may suggest uterine or ovarian dysfunction and need evaluation.

Phases of Menstrual Cycle

• The menstrual cycle is divided into two main phases separated by ovulation.
• These phases are the follicular phase and the luteal phase.

Follicular Phase

• This phase begins on the first day of menstrual bleeding.
• It ends on the day of ovulation.
• During this period, a dominant ovarian follicle grows and matures.
• It is therefore called the follicular phase.
• It includes the menstrual phase, when bleeding occurs.
• It also includes the proliferative phase, when the endometrium regenerates and thickens.
• It is also known as the preovulatory phase.

Luteal Phase

• This phase starts after ovulation and continues until the next menstruation.
• The ruptured follicle becomes the corpus luteum.
• The corpus luteum secretes mainly progesterone and regulates this phase.
• The endometrium becomes glandular and secretory.
• Hence, it is also called the secretory phase.
• It is also known as the postovulatory phase.

Length of Each Phase of Cycle

• In a typical 28-day cycle, the follicular phase lasts about days 1 to 14.
• The luteal phase usually lasts about days 15 to 28.
• Menstrual bleeding occurs in the early part of the follicular phase.
• Ovulation usually occurs near the middle of the cycle.
• More precisely, ovulation occurs at the end of the proliferative phase and just before the luteal phase begins.
• Differences in total cycle length mainly result from changes in the follicular phase.
• The time required for follicular growth can vary between cycles.
• Once ovulation occurs, menstruation usually begins about 14 days later if pregnancy does not occur.
• Therefore, the luteal phase is relatively constant in duration.

• Some descriptions divide the cycle into bleeding, follicular, ovulatory, and luteal phases.
• However, bleeding is part of the follicular phase.

• Ovulation is an event, not a separate phase.

Changes in Reproductive Organs in Menstrual Cycle

Changes in the Follicular Phase (Menstrual and Proliferative Phase)

Ovarian Changes

• During the follicular phase, several follicles begin to grow in the ovary.
• Usually, one becomes the dominant follicle by about day 4.
• The dominant follicle enlarges and matures progressively.
• Granulosa cells and theca interna cells proliferate and secrete increasing amounts of estrogen.
• The fluid-filled antrum enlarges as follicular fluid volume rises.
• Near day 14 of a 28-day cycle, the mature follicle ruptures and releases the oocyte during ovulation.

Uterine Changes

• In the early follicular phase, menstrual bleeding causes shedding of the functional layer of the endometrium.
• After menstruation, rising estrogen from the developing follicle stimulates repair and growth of the uterine lining.
• From about day 5 to day 14, the endometrium increases in thickness.
• Endometrial cells undergo hyperplasia and hypertrophy.
• The mucosa becomes larger and more organized.
• Endometrial glands lengthen and remain relatively straight.
• These glands are lined by columnar epithelium.
• Blood supply increases through growth and elongation of spiral arteries.
• Enlarged veins also develop within the endometrium.
• Improved vascularity supports further tissue growth and nutrient delivery.
• Myometrial excitability increases under estrogen influence.
• Because endometrial growth is the dominant feature, this period is called the proliferative phase.
• It is also called the preovulatory phase because it occurs before ovulation.

Change in Uterine Cervix

• Under estrogen influence, cervical mucus volume increases during the follicular phase.
• Cervical mucus becomes more alkaline, clear, and stretchable.
• This increased elasticity forms the basis of spinnbarkeit.
• Cervical epithelium also becomes more secretory.
• These changes facilitate sperm passage through the cervix.

Vaginal Changes

• In the vagina, estrogen causes epithelial cells to become more cornified.
• The cornification index rises progressively and peaks near ovulation.

Changes in the Luteal Phase (Secretory Phase)

Ovarian Changes

• The luteal phase begins immediately after ovulation.
• The ruptured follicle first fills with blood and is called the corpus hemorrhagicum.
• Granulosa and theca cells then enlarge and undergo luteinization.
• This forms the corpus luteum, a temporary endocrine gland.
• The corpus luteum secretes mainly progesterone and smaller amounts of estrogen.
• If pregnancy occurs, it persists temporarily.
• If pregnancy does not occur, it regresses near the end of the cycle and becomes the corpus albicans.

Uterine Changes

• Progesterone is the dominant hormone of this phase.
• Under progesterone and estrogen influence, the endometrium enters the secretory phase.
• Uterine glands become long, coiled, and tortuous.
• Glandular cells accumulate glycogen and secrete nutrient-rich fluid.
• These secretions help prepare the uterus for implantation.
• Endometrial blood supply increases further.
• Spiral arteries become elongated and more tortuous.
• The endometrium becomes thicker, softer, and edematous.
• Endometrial veins enlarge and may form venous lakes.
• Myometrial excitability decreases, reducing uterine contractions.
• If fertilization does not occur, the corpus luteum regresses.
• Levels of progesterone and estrogen fall sharply.
• Spiral arteries undergo intermittent vasoconstriction.
• Reduced blood flow causes ischemia and focal necrosis of the endometrium.
• Necrotic areas merge, and the superficial endometrium begins to detach.
• This leads to the onset of menstruation at the end of the phase.

Change in Cervical Mucous

• Under progesterone influence, cervical mucus becomes thick and less stretchable.
• Its alkalinity and water content decrease.
• This makes sperm passage more difficult.

Vaginal Changes

• Progesterone causes proliferation of vaginal epithelium.
• Vaginal secretions become thicker.
• Leukocyte infiltration increases.
• Cornification of epithelial cells decreases compared with the follicular phase.

Mechanism of Menstrual Bleeding

• When the corpus luteum regresses, progesterone and estrogen levels fall.
• Loss of hormonal support causes breakdown of the endometrium.
• Spiral arteries constrict, reducing blood supply and causing ischemia.
• Necrotic areas merge with hemorrhage and tissue shedding, producing menstrual bleeding.

Mechanism

• Menstruation is initiated by a fall in ovarian steroid hormones, mainly progesterone and estrogen, after regression of the corpus luteum.
• Hormonal withdrawal destabilizes lysosomal membranes in endometrial cells, releasing proteolytic enzymes.
• These enzymes break down the functional layer of the endometrium.
• Increased production of prostaglandin F2 alpha causes constriction of spiral arteries.
• Arterial spasm reduces blood flow and produces temporary ischemia.
• Ischemic tissue undergoes local necrosis.
• Necrotic areas merge, causing shedding of the superficial endometrium.
• The shed tissue mixed with blood appears as menstrual flow.

Amount of Loss

During a normal menstruation, about 30–130 mL of blood is lost. The menstrual blood contains tissue debris, prostaglandins, and fibrinolysin. Increased menstrual loss is known as menorrhagia and decreased loss as hypomenorrhea.

Hormonal Changes in Menstrual Cycle

Estrogen

Estrogen has two peaks in the menstrual cycle.

1. The fist peak, which is the major peak, occurs about 48 hours before ovulation and the second peak, which the minor peak, occurs in the post-midluteal phase (Fig. 69.1B).
2. With the growth of ovarian follicle, estrogen concentration slowly increases in the early part of follicular phase. The concentration rises rapidly from 8th day of cycle to reach the peak about one or two days before ovulation. The concentration decreases thereafter and decreases further after ovulation.
3. About two days after ovulation (after the formation of corpus luteum), again estrogen concentration increases slowly to reach a smaller peak that occurs just after the midsecretory phase.

Progesterone

Progesterone concentration is minimal in the proliferative phase.

1. It starts rising following ovulation and reaches peak in 4 to 5 days after ovulation.
2. The peak is maintained till corpus luteum is active.
3. With regression of corpus luteum, progesterone concentration decreases toward the end of luteal phase.

LH

The concentration of Luteiuizing hormone (LH) remains low almost throughout the proliferative phase. However, about a day before ovulation, the secretion of LH increases sharply to reach the peak about 8–10 hours before ovulation. This is called LH surge (see below). Then, it declines fast in 24–48 hours and remains low in rest of the secretory phase (Fig. 69.1A).

FSH

Follicle-stimulating hormone (FSH) secretion increases in the early part of the follicular phase (during menstrual bleeding), and then declines slowly. Synchronous with the rise in LH, secretion of FSH rises toward ovulation and thereafter the pattern of change in FSH is similar with LH pattern.

Inhibins

The pattern of change in concentration of inhibin B coincides with the change in concentration of FSH, whereas the concentration of inhibin A coincides with the pattern of progesterone.

Ovulation

Ovulation is the process of release of ovum (oocyte) from the ovary that results from rupture of Graafian follicle at the end of the follicular phase of the menstrual cycle. Usually, ovulation occurs on 14th day in a 28 days cycle. However, if the cycle length is altered, ovulation occurs 14 days before the onset of menstrual bleeding as the duration of luteal phase (which is 14 days) always remains constant.

Mechanism of Ovulation

Ovulation occurs due to midcycle LH surge.

1. LH surge occurs due to high rise in estrogen concentration toward the later part of follicular phase that provides a positive feedback effects on LH secretion from pituitary.
2. Normally, a mild to moderate increase in estrogen for a brief period is inhibitory on LH secretion.
3. Two-days prior to ovulation, estrogen concentration increases to a higher level and when this high concentration is maintained for about 36 hours, the process of ovulation is initiated.
4. A series of biochemical and morphological changes occur in ovarian follicle that culminates in follicular rupture.
5. Three chemical substances are involved in rupture of ovarian follicle: prostaglandins, cyclin D2 (a protein that regulates cell cycle), and C-EBP (CCAAT-enhancer binding protein). Decreased formation of these chemicals in ovary has been demonstrated to prevent ovulation in mice.

Steps of Follicular Rupture

1. LH surge increases release of prostaglandins and bradykinin that increase the ovarian blood flow. Thus, follicular blood flow increases.
2. The dominant follicle becomes highly vascularized and edematous. This increases the size of the follicle to about 25 mm.
3. Follicular blood flow also increases antral fluid volume, which in turn exerts pressure on the surrounding granulosa cells. The cumulus-oophorus complex gets detached from the follicular wall.
4. The basement membrane that separates granulosa cells and theca cells disintegrates due to intrafollicular pressure and the effects of proteolytic enzymes.
5. LH promotes synthesis of plasminogen activator by granulosa and theca cells, which causes conversion of plasminogen to plasmin. Plasmin causes proteolysis of follicular wall. Plasmin also activates the synthesis of collagenase that causes destruction of connective tissue matrix of the follicular wall and adjacent ovarian capsule.
6. Increased intrafollicular pressure and degeneration of the follicular wall facilitate the rupture of the follicle, which results in expulsion of oocyte from the follicle and the ovary.
7. FSH surge is not essential for ovulation (Application Box 69. 2).

Indicators of Ovulation

It is important to know the day of ovulation for its physiological and clinical significance. The indicators of ovulation are as follows:

1. Rise in of basal body temperature: The basal body temperature (BBT) increases during ovulation by about 0.5°C. Accurate charting of this temperature can exactly detect the day of ovulation.
   • It is recorded orally, early in the morning before getting up of the bed, and before taking any drink or washing the mouth.
   • The increase in body temperature is due to the influence of progesterone that starts increasing with the beginning of secretory phase. Progesterone is thermogenic.
2. Fleeting lower abdominal pain (mittelschmerz): With ovulation, bleeding occurs into the antrum of the follicle.
   • Small amount of blood also escapes into the abdominal cavity, which causes peritoneal irritation and produces fleeting (short-lived) lower abdominal pain.
   • This is called as mittelschmerz.
3. Vaginal discharge (spotting): There may be transitory increase in vaginal discharge during ovulation.
   • When rise in BBT is associated with mittelschmerz and spotting, they are collectively called as ovulation cascade.
   • If all the three features are present, occurrence of ovulation is almost confirmed.
4. Spinnbarkeit: In the proliferative phase, estrogen makes the cervical mucous thin and alkaline.
   • With the beginning of secretory phase, progesterone secreted from corpus luteum makes the cervical mucous thick and tenacious. Thus, uterine mucous is thinnest at the time of ovulation and its elasticity is maximal.
   • Therefore, a drop of cervical mucous collected at the time of ovulation can be stretched to as long as 10 cm or more like a thread. This elastic nature of the mucous is called spinnbarkeit.
   • Decreased elasticity indicates ovulation has already taken place.
5. Fern test: Under the effect of estrogen, the cervical mucous before ovulation forms an arborizing fern like pattern, when the mucous is spread on a slide.
   • This is confirmed by microscopic examination of the mucous smear.
   • Following ovulation, due to progesterone effect, the mucous become thick and fern pattern is not observed in smear of the mucous.
6. Laparoscopic observation: Demonstrating ovum in the abdominal cavity by laparoscopy confirms ovulation.
7. Demonstration of LH peak: LH surge occurs just prior to ovulation. Therefore, daily estimation of plasma LH in the periovulatory period will accurately detect the day of ovulation.

Physiological Importance

Determination of day of ovulation helps in family planning.

1. The life span of ovum is about 72 hours.
2. Therefore, those who are desirous of a child, should have regular sexual act in the periovulatory period (day of ovulation, and two days before and after the ovulation).
3. Those who want to avoid pregnancy, should not have unprotected sexual act during the unsafe period (day of ovulation, four days before and after ovulation) of the cycle (Fig. 69.3).
4. Thus, it helps in planning both conception and contraception (for details, see “Female Contraceptives”).

Disorders of Menstrual Cycle and Ovulation

Amenorrhea

Absence of menstrual cycle is referred to as amenorrhea. Amenorrhea is broadly classified into two categories: primary and secondary; each category subdivided into physiological and pathological.

Primary Amenorrhea

When menstruation has never occurred, the condition is called primary amenorrhea. There are physiological and pathological causes of primary amenorrhea.

Physiological Primary Amenorrhea

Amenorrhea occurs in many physiological conditions. Physiological amenorrhea is more common than pathological amenorrhea. The causes of physiological amenorrhea are:

1. Before puberty: Amenorrhea is normal in childhood and prepubertal age. Usually, menstruation starts at the age of 12–14 years.
2. Constitutional amenorrhea: Though menstrual cycle starts normally by the age of 16 years, sometimes it may not occur even at the age of 18 years or more, without there being any abnormality. This is called constitutional amenorrhea.

Pathological Primary Amenorrhea

When menstrual cycle does not start till the age of 18 years due to some prevailing disease, the condition is called pathological primary amenorrhea.

1. It usually occurs due to congenital and genetic defects. Examples are Turner syndrome, Kallman syndrome, etc.
2. Congenital malformations of reproductive tract like absence of uterus can also cause primary amenorrhea.

Secondary Amenorrhea

When menstrual cycle stops in a woman who had normal cycles before, the condition is called secondary amenorrhea. There are physiological and secondary causes.

Physiological Secondary Amenorrhea

Physiological causes of secondary amenorrhea are more common than pathological causes.

1. Peri-pubertal amenorrhea: In first one to two years of onset of menarche, menstrual cycles are often anovulatory and therefore irregular. Menstruation does not occur even for 2–4 consecutive cycles. This is called peripubertal amenorrhea. This very common till the full pubertal and reproductive developments occur and is regarded as normal.
2. Pregnancy: Pregnancy is the commonest cause of secondary amenorrhea. It is so common amongst all forms of amenorrhea that before investigating for the causes of amenorrhea, first, pregnancy should be ruled out.
3. Lactation: The prolactin concentration is high in the plasma of a lactating mother. Prolactin inhibits the secretion of gonadotropin-releasing hormone (GnRH), and therefore, ovulation is prevented. This is called lactational amenorrhea. This is the physiological basis of contraception in a lactating woman.
4. Emotional disturbance: Psychological trauma frequently causes amenorrhea by disrupting hypothalamic release of GnRH via limbic-hypothalamic connections.
5. Change in environment: Sudden change of place, especially exposure to extremes of climates is known to produce amenorrhea during the acclimatization period.
6. Menopause: Menstrual cycle ceases at menopause. This occurs due to failure of the ovary, to respond to gonadotropic stimuli. It occurs usually between the ages of 45–50 years. Menstrual cycles become initially irregular for 2–6 months before completely stopping at menopause.

Pathological Secondary Amenorrhea

Pathological secondary amenorrhea occurs due to a defect in hypothalamus, pituitary, ovary and uterus or due to a systemic disease or chronic use of some drugs.

1. Hypothalamic disorders: Hypothalamic diseases resulting in decreased secretion of GnRH leads to amenorrhea. The reduction in frequency of GnRH pulses rather than the absolute decrease in concentration of GnRH is the cause of hypothalamic amenorrhea. Recently, it has been observed that this occurs due to increased opioid activity and treatment with opioid blockers like naltrexone cures hypothalamic amenorrhea.
2. Pituitary disorders: Tumors and other diseases of pituitary (hypopituitarism) resulting in decreased secretion of gonadotropins leads to amenorrhea. Examples are Sheehan’s syndrome (post-partum ischemic necrosis of anterior pituitary due to severe hemorrhage during childbirth) and Simmond’s syndrome (complete destruction of anterior pituitary) etc.
3. Ovarian diseases: Diseases that decrease the production of estrogen and progesterone, frequently lead to amenorrhea. In Stein-Leventhal syndrome (polycystic ovarian disease), amenorrhea occurs due to abnormal production of hormone leading to high LH-FSH ratio and high androgen level.
4. Uterine pathology: Congenital absence of uterus, underdeveloped uterus and severe infective or noninfective endometritis produce amenorrhea.
5. Systemic illness: Amenorrhea occurs in chronic illnesses like chronic hypothyroidism, chronic renal failure and cirrhosis of liver. Any systemic illness that leads to cachexia may also cause amenorrhea.
6. Drugs: Phenothiazine derivatives, reserpine, ganglion blocking agents and estrogen-progesterone preparations (pill contraceptives) are common drugs that prevent menstrual cycles. They mainly act by inhibiting hypothalamic release of GnRH.

Anovulation

Absence of ovulation during a menstrual cycle is called anovulatory cycle.

1. Following menarche, menstrual cycles may be anovulatory for first 1 to 2 years.
2. Few cycles may also be anovulatory in lactating woman, and about six months before menopause.
3. Anovulation also occurs in severe strenuous exercise or severer job related stress.
4. Except these physiological situations, anovulation is abnormal and occurs mainly due to hormonal deficiencies.

Treatment of Amenorrhea and Anovulation

If amenorrhea is due to hypothalamo-pituitary defects, pulsatile administration of GnRH gives successful result. In hypopituitarism, sequential administration of FSH and hCG is useful. If amenorrhea is due to pituitary tumor, their surgical removal should be considered. Clomiphene, that binds with estrogen receptors and blocks estrogen action, induces ovulation. Clomiphene increases LH and FSH secretion by reducing the negative effects of estrogen. For uterine pathologies, corrective surgeries should be performed.

Hypomenorrhea and Oligomenorrhea

Decreased menstrual bleeding in duration or amount or both is called hypomenorrhea. It may be constitutional, or due to uterine pathology or due to hormonal disorders. Decreased frequency (cycle more than 35 days) of menstrual cycle is called oligomenorrhea. Usually, oligomenorrhea occurs in ovarian diseases in which menstruation is irregular and infrequent.

Dysmenorrhea

Dysmenorrhea means painful menstrual bleeding. It is classified into two categories:

1. Primary dysmenorrhea in which there is no visible pelvic pathology, and
2. Secondary dysmenorrhea in which a uterine or pelvic pathology is associated with it. Usually, it occurs due to passage of clots in flow.

Dysmenorrhea occurs due to accumulation of prostaglandins in the uterine fluid. Therefore, use of prostaglandin inhibitors usually gives relief from dysmenorrhea.

Menorrhagia, Metrorrhagia, and Polymenorrhea

Menorrhagia

Increased menstrual bleeding in amount, duration or both is called menorrhagia.

1. It is generally caused by conditions that affect uterus and its vascular apparatus rather than any ovarian dysfunction.
2. Or, sometimes it may be a manifestation of coagulation disorder.

Metrorrhagia

Bleeding occurring between the periods (acyclical and irregular) is called metrorrhagia. It usually indicates a surface lesion in the genital tract, which may be benign or malignant.

Polymenorrhea

When menstrual cycle occurs frequently (less than 21 days), it is called polymenorrhea. Usually, the amount and duration of bleeding remain normal.

Premenstrual Syndrome

Few women develop some nonspecific features about a week before the onset of menstrual bleeding that are combinedly called as premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD).

Features: The usual features are edema, painful or swollen breasts, depression, loss of concentration, irritability, headache, behavioral changes, and emotional disturbances. These features disappear within 1–3 days after the start of menstruation.

Etiology: Though the salt and water retention has mainly been attributed to PMS, the exact cause of it is not known. Recently, it has been proposed that PMS occurs due to an excess and complex interplay between the sex steroids and brain neurotransmitters.

Treatment: Treatment with drugs that prematurely terminate luteal phase of the cycle does not give any substantial relieve, which indicates that the PMS is not due to hormonal imbalance. Also, the plasma concentrations of hormones usually found to be normal in these patients. However, treatment with alprazolam (minor tranquilizer), prozac (serotonin uptake inhibitor) and GnRH agonist give some relief. This proves the hypothesis that PMS is due to the complex interplay between the gonadal steroids and neurotransmitters in the brain.

Anorexia Nervosa

It is a complex behavioral disorder in women which manifests as severe anorexia (loss of food intake) associated with functional abnormalities.

1. Amenorrhea is seen in 30–40% of cases.
2. Patient is grossly emaciated.
3. Emaciation (low body fat) and stress inhibit LH secretion through endorphins.
4. Pubic hair development and breast development usually remain unaffected.