Many misbeliefs and taboos have surrounded the menstruation throughout the recorded history. Fortunately, the scientific research has been able to demonstrate the complex cyclical interplay between hormones and uterus that leads to visible loss of endometrial tissue and blood called as menstruation. The purpose of these changes is actually to prepare the endometrium for the implantation and growth of the fertilized ovum, if fertilization takes place. If the fertilization does not take place, the endometrium is thrown out in the disappointment. Indeed this cyclical bleeding is called by some as the ‘weeping of the disappointed uterus.1 But with the motto of never to lose hope, uterus starts preparing itself for another chance.
Menstruation is the cyclical uterine bleeding occurring during the reproductive age between menarche to menopause. The first menstrual period, menarche, generally occurs between 10-16 years with 13 years being the average age in the Indian scenario. Menopause is the complete cessation of menses. The average age of menopause in India is 48 years.1 Normal menstruation represents the cyclic shedding of secretory endometrium and is essentially a progesterone withdrawal bleeding caused by degeneration of corpus luteum if the ovum is not fertilized.2
The endometrium is structurally composed of glands and stroma. It is divided into two layers, a superficial functional layer ‘decidua functionalis’ (further divided into ‘stratum compactum’ and ‘stratum spongiosum’) responding to the hormones and a basal layer ‘decidua basalis’ responsible for the regeneration of endometrium.
Under the influence of monthly cyclic production of estrogen and progesterone by ovaries, endometrium undergoes cyclic changes through the following phases:3
- Proliferative phase
- Secretory phase
- Menstrual phase.
Proliferative Phase
It corresponds to follicular phase of ovarian cycle. It follows the menstrual phase and concludes at ovulation. During the proliferative phase, the estrogen from the growing follicle causes regeneration of the endometrium from the basalis layer. The surface is covered with the epithelium that grows from the glands and stroma in the basalis. Vascular endothelial growth factor (VEGF) is a highly potent endothelial mitogen 2produced by the endometrium in response to the rising estrogen and associated hypoxia.1 It plays a major role in angiogenesis and endometrial repair. Short, narrow and straight glands become longer and tortuous due to estrogen influence while the stroma becomes dense and compact. At the time of ovulation endometrium is 3 to 5 mm thick. This phase is of variable length depending upon the event of ovulation.
Secretory Phase
This is the progestational phase of endometrial cycle which begins after ovulation. It corresponds to luteal phase of ovarian cycle. Secretory phase extends from ovulation till the onset of next menses. The progesterone (from corpus luteum) dominated secretory phase brings about secretory changes in the estrogen primed endometrium with the primary aim to produce appropriate environment for implantation and providing nutrition to the fertilized ovum. The progesterone leads to accumulation of protein-rich eosinophilic material in the glands causing increasing tortuosity and also bringing about pseudostratified appearance in the glandular epithelium. On histopathological examination this gives typical ‘saw-toothed’ and ‘cork-screw’ appearance in the cross-section.1 The stroma becomes more edematous and vascular. This change is described as ‘pseudo-decidualization’.
At the peak of the secretory phase about one week after ovulation the endometrial thickness is about 5 to 6 mm.3 If ovum does not get fertilized, the corpus luteum degenerates and menstruation starts around 14th day after ovulation. This phase is fairly constant. During this phase there is increase in basal body temperature 0.5 to 1°F above the preovulatory level, due to thermogenic action of progesterone. It is considered as presumptive evidence of functioning corpus luteum and hence ovulation.4
Menstruation Phase
Shedding of endometrium takes place during this phase and it lasts for about five days.
Mechanism of Normal Menstruation
Unique feature of endometrium is the presence of spiral arterioles which arise from basal arteries at right angles and are directed towards the uterine cavity. Spiral arterioles are endarteries supplying the limited area of endometrium without anastomosis. During proliferative phase these arterioles grow from basal layer to the superficial layer. During secretory phase there is marked increase in the length and coiling of the arterioles. The key event in menstruation as postulated by Markee (1950) is the intense vasoconstriction of spiral arterioles about 24 hours prior to menstruation, resulting in ischaemic necrosis of the endometrial segment supplied by them.5 This necrotic endometrium gets separated with accumulation of blood pools underneath and is expelled out.
Intense vasospasm is probably brought about by prostaglandins having vasoconstrictive action. However, the experimental models have strongly upheld the concept of ‘threshold hormone level’ for initiation of bleeding and prostaglandin mediated vasospasm is now believed to be a later protective phenomenon to stop 3the bleeding.1 As the hormones fall below the threshold, the endometrium fails to sustain, undergoing a sudden shrinkage. This needs shortening of the spiral arterioles by increasing and tightening their coils. This in turn retards the circulation in these vessels causing ischaemic necrosis of the areas supplied by these endarterioles. Thus, the endometrial shedding begins at various places with the bleeding lasting over 4-5 days period.
Menstrual discharge contains mainly the desquamated endometrium, altered blood, mucus, leucocytes, exfoliated vaginal epithelial cells, prostaglandins and enzymes. Fibrinolysin is released along with necrotic endometrial material and therefore menstrual discharge is nonclotting and easily expelled out through cervix. Presence of leucocytes make the uterus highly resistant to infection during menstruation even though endometrial surfaces are denuded. These are the physiological protective actions for safeguarding the reproductive function of the genital tract.
The menstrual flow stops as a result of combined effect of prolonged vasoconstriction, myometrial contractions and hemostatic plug formation of aggregated platelets and fibrin.6,7
Regeneration of endometrium begins within 48 hours of onset of bleeding (Ferenczy, 1976).7 Re-epithelization commences from basal layer of endometrium and is usually completed by 3rd or 4th day.7 Rate of re-epithelization is probably dependent upon the amount of estrogenic stimulation which in turn depends upon the rate of growth of follicles developing in the ovary.
Role of Prostaglandins in Normal Menstruation
The endometrium and to some extent myometrium synthesizes the various prostaglandins from arachidonic acid. Rate limiting step in prostaglandin synthesis is the activation of enzyme phospholipase A2.7 Phospholipase A2 is present in inactive form in the lysosomes present in the endometrium. Progesterone promotes the formation of lysosomes in the endometrium. Progesterone has got stabilizing effect and estrogens have labilizing effect on lysosomes. Withdrawal of progesterone preceding menstruation probably causes breakdown of lysosomes and release of phospholipase A2 which acts upon the phospholipids in the cell walls and produces large amounts of arachidonic acid resulting in initiation of prostanoid cascade and the synthesis of various prostaglandins. PGF2α plays a major role in the menstrual pathophysiology. PGF2α causes myometrial contraction, vasoconstriction and platelet aggregation. PGE2 causes myometrial contraction but causes vasodilatation and has platelet antiaggregatory activity. Prostacycline (PGI2) produces myometrial relaxation, vasodilatation and also inhibits platelet activity. In the proliferative phase of normal menstruation the synthesis of PGF2α and PGE2 are in 1:1 proportion. However, in the secretory phase there is increase in PGF2α secretion and PGF2α: PGE2 ratio becomes 2:1 causing vasoconstriction, platelet aggregation and myometrial contraction as predominant actions. Thus, relative proportion of different prostaglandins in the endometrium is probably responsible for blood flow and menstrual pain.
REGULATION OF MENSTRUAL CYCLE (ENDOCRINE CONTROL)
The Hypothalamo-pituitary Axis
The endometrial cycle is under control of ovarian cycle which in turn is governed by Hypothalamo-pituitary axis (Fig. 1.1).
The hypothalamus secretes the gonadotropin releasing hormone (GnRH), with varying frequency and amplitude leading to the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. The follicular phase shows high amplitude more frequent pulses with frequency increasing before LH surge with dominance of FSH. The luteal phase has low amplitude less frequent pulses leading to the predominance of LH. One pulse every hour is typical of follicular phase and one pulse every 2 to 3 hours is typical of luteal phase.8
The Ovarian Cycle
The primordial germ cells arise at 5-6 weeks of intrauterine life in the yolk sac, allantois and hindgut and migrate to the genital ridge to lie in the future ovaries.1 They undergo rapid multiplication and the number is around 6-7 millions by 16-20 weeks of intrauterine gestation. Rapid degeneration thereafter leaves behind about 2 million primordial follicles by birth. Atresia continues until puberty whereby only 3,00,000 follicles remain. Finally during the whole reproductive life of a woman only about 500 follicles will undergo maturation and ovulate.
Ovarian cycle comprises of two phases, follicular phase and luteal phase separated by the event of ovulation.
The Follicular Phase
It basically involves growth and maturation of the follicle, which results in formation of the hormones (Estrogen, Progesterone and Androgens) and a mature ovum capable of fertilization. It ends with ovulation.
In response to FSH, which begins to rise at the onset of follicular phase, a group of follicles is recruited.9 The number of the follicles that start growing appears to be determined by the size of the residual pool of the inactive primordial follicles 10. Follicular 5growth is a process best described by Peters as continuum.10 Only one of the follicles in the group responds best to the FSH stimulation due to its highest FSH receptor content and high intrafollicular estrogen levels.11 Other follicles have high androgenic environment and undergo atresia. The ‘Graffian follicle’ (Fig. 1.2) was described by Regnier de Graaf (1672) as a vesicle measuring 12-16 mm in diameter after puberty.4 The follicle starts from the primordial follicle stage, lined by a single layer of granulosa cells, and passes through the preantral and antral stages, finally to reach the preovulatory stage. The granulosa layer multiplies with the simultaneous differentiation and arrangement of the multilayered theca from the surrounding stroma.
The granulosa and theca cells form the ‘Two-Cell System’ (Fig. 1.3) responsible for the production of all three classes of Steroids—Estrogens, Progestogens and Androgens.12-16
This system has been postulated and accepted as the hormone synthesizing machinery by many authors. It consists of theca cell which synthesize androgenic precursors from cholesterol under the influence of LH, which then diffuse into the adjacent granulosa cells. The granulosa cells convert these androgens into estrogens through the process of aromatization. LH governs the entry of cholesterol (the precursor for steroidogenesis) into the mitochondria and hence the ovarian steroidogenesis is always LH-dependent.11
The FSH initiates steroidogenesis (estrogen 6production) and stimulates granulosa cell growth 17 FSH also induces LH receptor development on granulosa cells of large antral follicles with estrogen serving as the chief co-ordinator.11 The growing follicles secrete inhibin, a peptide, synthesized by granulosa cells in response to FSH. Inhibin is secreted in the follicular fluid and ovarian venous effluent.18,19 Inhibin has multiple inhibitory effects on gonadotropin secretion. It can stop synthesis and secretion of FSH, prevent GnRH receptor upregulation, decrease the number of GnRH receptors present and at high concentration can cause degradation of gonadotropins.1,20 FSH and inhibin share a reciprocal relationship, FSH stimulating the secretion of inhibin from the granulosa cells and inhibin in turn suppressing the FSH secretion from pituitary.21,22 The fate of the antral follicle is delicately balanced by the intrafollicular hormone levels. At low concentrations androgens enhance their own aromatization leading to estrogen formation but at higher levels the capacity of aromatization falls inadequate and the follicle undergoes atresia due to its high androgenic levels.13 The dominant follicle continues to grow inspite of falling FSH due to its high concentration of the FSH receptors and high estrogenic environment, which make it more sensitive to the available FSH. Antral follicles with highest estrogen concentration and lowest Androgen: Estrogen ratios are likely to house a healthy oocyte.11 Other less important feedbacks take place through activin which stimulates FSH secretion and follistatin which suppresses FSH secretion by combining with and inactivating activin.11 Activin has opposite actions to inhibin, like stimulation of FSH release and increasing GnRH receptors.23,24 Many other peptides like IGF-I, IGF-II, etc. have been implicated with complex roles.
The Ovulation
Declining FSH as a result of increasing inhibin appears to rescue itself from this suppression at midcycle, causing increased FSH secretion again. This increasing FSH secretion along with estrogen peak secretion from developing follicles brings a subsequent rapid increase in LH secretion called as LH-Surge (Fig. 1.4).11,1
The Mechanism of LH Surge
Experimental evidence suggests that, the positive feedback of estrogen on the pituitary involves the increase in the GnRH receptor concentration on the pituitary.25 This increase in the receptor concentration on the pituitary and a rise in the GnRH released from hypothalamus accompanies LH surge, indicating that estrogen positive feedback operates at both pituitary and hypothalamic sites.26 At very high levels, estrogen combines with inhibin for suppression of FSH that is profound and sustained. In contrast, the influence of estrogen on LH release varies with concentration and duration of exposure. At low levels estrogen commands a negative feedback relationship with the LH while at high levels estrogen is capable of exerting a positive stimulatory feedback effect on LH release resulting into the LH surge (Fig 1.4).27 Progesterone also acts at both sites, but having inhibitory action on hypothalamus and stimulatory action on pituitary, like that of estrogen.287
The Release of the Ovum
LH surge starts progesterone synthesis just before ovulation with sudden rapid changes in the pre-ovulatory follicle. Follicle accumulates liquor folliculi and distends. It is then shifted near the ovarian surface where at the weakest area (stigma) the wall is breached due to the action of proteolytic enzyme and the ovum escapes out. Collagenase is the locally synthesized proteolytic enzyme causing the breach, synthesized due to activation of plasmin.11 Prostaglandin PGF2α synthesized locally pushes out the ovum by causing gentle contractions of the ovarian micromusculature.1
This causes ovulation pain experienced by some women, known as ‘Mittelschmerz’.4 Anovulatory cycles are, therefore, always painless.
Luteal Phase
After the release of ovum the follicle collapses and forms the ‘corpus luteum’ (the initial red hemorrhagic body is called the ‘corpus hemorrhagicum’). Development of corpus luteum is complete within 5 days by which it is already functioning and reaches its peak function in next 3-4 days. The function wanes thereafter as degeneration starts 4-5 days before next expected menstrual period if the fertilization does not take place. The corpus luteum appears yellow to the naked-eye examination due to the presence of lipoids.1 It finally undergoes hyaline degeneration to form ‘corpus albicans’.8
9The corpus luteum secretes predominantly progesterone along with estrogens and little amount of androgens too.
CRITERIA FOR NORMAL MENSTRUAL CYCLE
Menstrual cycle is judged by three clinical parameters—cycle length, duration of bleeding and amount of blood loss.
Cycle Length
It is the interval between the first day of one period and the first day of the next.4 During active reproductive years, menstruation occurs at approximately 28 +/- 7 days. Each woman has her own rhythm which may change after marriage or childbirth.1 However, Treloar et al reported at University of Minnesota in his prospective study over 30 years in Caucasian women that the cycle length usually varies by 1 to 2 days each month and only 50 percent of women have cycles within 26-30 days range. Median cycle length declines from 28.87 (+/- 2.75) days at the age of 20 years to median of 26.8 (+/-2) days by 40 years of age.29 In reference to this study, in general, cycles with length less than 24 days are considered polymenorrhea and those with more than 35 days are considered oligomenorrhea.
Regularity of cycle length depends upon hypothalamo–pituitary-ovarian axis. The immediate postmenarche cycles are irregular and long due to immaturity of hypothalamus and pituitary as a result of which regular ovulation is yet to be established. Again in perimenopausal period, cycles become irregular and mostly longer due to decreased number of follicles with increased resistance to gonadotropin stimulation.7
Duration of Menstrual Blood Loss
As per Guillebaud and Bonner (1978), normal range of duration of bleeding is 2 to 7 days with average of 5 days.30 Shorter (hypomenorrhea) or longer (hypermenorrhea) than this is considered as abnormal.
Menstrual Blood Loss (MBL)
Average blood loss per cycle is considered to be about 35 to 40 cc. This is equivalent to a daily loss of 0.6- 0.7 mg of iron throughout each month.1 According to Rybo et al (1985) parity has a small effect on MBL, multiparas having a slightly higher average loss than nulliparas.31 WHO Report (1987) mentions that in Western European populations, the average blood loss during menstruation varies from 31 to 39 ml while in Chinese and Japanese populations it is increased to 47-54 ml and 50-56 ml respectively.32 In Swedish population, Hallberg et al (1966), observed significant increase in the incidence of iron deficiency anemia when the MBL was 80 ml or more.33
10Correlation of duration of menstruation and MBL is debatable. Haynes et al34 (1977) found no correlation between MBL and duration of menses while Rybo35 (1966) found the mean MBL to be greater than 50 ml, if the duration of menstruation exceeded 7 days.34,35
Van Eijkeren et al (1986) showed that the total blood loss can be estimated from the total hemoglobin extracted from all tampons, towels, and other material used and measured objectively by the alkaline hematin.36 Hallberg and Nilsson have described a method to measure the iron and blood loss during menstruation. This method involves collection of tampons and pads which are treated with 5 percent NaOH. This converts hemoglobin to alkaline hematin which can be measured spectrophotometrically.37,38 This method though simple and accurate, has not gained wide acceptance as it lacks practicality. Therefore today, we do not have any objective method that can be used in day to day practice for estimation of menstrual blood loss. Woman's self-assessment about blood loss, taking into consideration the number of pads, tampons she has to use during menstruation can be of value in judging the MBL. Women with reasonable standards of cleanliness use 3 diapers or tampons in 24 hours, 2 during the day and 1 during the night, making a total requirement of 12-15 for the normal menstrual period.1 However, Chimbira et al found no correlation between the measured MBL and the number of tampons and towels used and the patient's self-assessment.39 The woman's self-assessment about MBL is subjective and depends upon various factors like, her attitude towards menstruation, socio-economic and psychological background, hygienic habits and absorptive power of the sanitary pads, tampons used. However, evidence of anemia and history of passage of clots during menstruation is suggestive of excessive MBL.
Thus, the menstrual cycle is said to be within normal limits if,
- Cycle length is in the range of 21 to 35 days with mean of 28 days
- Duration of MBL is in the range of 2 to 7 days with mean of 5 days
- Amount of MBL is up to 80 ml with average around 40 ml
Any deviation from normal either in length, duration or amount of MBL is considered abnormal uterine bleeding or abnormal menstruation. Following are the terminologies used to describe abnormal bleeding patterns.8
Polymenorrhea is uterine bleeding that occurs at regular interval less than 21 days apart.
Oligomenorrhea is infrequent uterine bleeding that occurs at intervals more than 35 days apart.
Menorrhagia is prolonged (>7 days) and /or excessive (>80 ml) uterine bleeding that occurs at regular intervals.
Metrorrhagia is uterine bleeding that occurs at irregular but frequent intervals, the amount of uterine bleeding is variable and duration of flow is often prolonged.
Menometrorrhagia is prolonged uterine bleeding that occurs at irregular intervals.
Intermenstrual bleeding is bleeding of variable amounts that occurs between regular menstrual periods.
11Etiology behind these menstrual abnormalities is wide and vast. Even though diseases of the reproductive tract right from inflammation to neoplasm and pregnancy complications constitute the major etiological factors during reproductive period, dysfunctional uterine bleeding is also equally common at all ages (Sutherland, 1949) and can present with any type of bleeding pattern.40
Physiological dysfunction of menstrual mechanism is commonly seen for about 2 years after menarche and about 3 years before menopause.8 Immaturity of the hypothalamus and pituitary causes irregular cycles in the post-menarchal period. Menopause is preceded by gradual oligomenorrhea with gradual hypomenorrhea (gradual reduction in duration of bleeding) owing to decreasing number of follicles in the ovary with increased resistance to gonadotropins.
Some women experience intermenstrual bleeding at the time of ovulation. This is a physiological dysfunctional uterine bleeding as it is caused by the physiological event, i.e. drop in the estrogen levels at the time of ovulation.
The abnormal bleeding pattern at any age needs attention and should never be regarded as physiological unless proved otherwise.
KEY POINTS
Physiology
- Proliferative phase in the menstrual cycle corresponds to the follicular phase of the ovarian cycle and concludes at ovulation.
- In the follicular phase estrogen from the growing follicle causes endometrial regeneration and growth.
- Aim of the follicular phase is to produce a mature ovum capable of fertilization.
- Secretory phase is the progestational phase of the menstrual cycle and corresponds with the luteal phase of the ovarian cycle.
- The aim of the secretory phase is to produce appropriate environment for the implantation of the fertilized ovum.
- In the absence of fertilization, menstrual bleeding starts due to progesterone withdrawal.
- As a result of coiling of the spiral arterioles (endarterioles), the endometrial tissue suffers hypoxia, undergoes necrosis and is thrown out.
- Prostaglandins play a major role in the menstrual physiology.
Endocrine Control
- The Hypothalamus secretes GnRH which acts on anterior pituitary gland and causes release of FSH and LH.
- FSH causes many follicles to grow, with maturation of one of them, having high estrogen receptor concentration and high intrafollicular estrogen levels.
- Two-cell system of theca and granulosa cell is responsible for the production of steroids.
- As the follicle grows, it secretes inhibin and causes suppression of FSH.
- Antral follicle with highest estrogen and lowest androgen content, houses a healthy oocyte.
- High estrogen exerts a positive feedback on LH release responsible for LH-surge at midcycle.
- Ovum is released as a result of breach in the capsular wall by proteolytic enzyme, collagenase.
- After ovulation, follicle collapses to form a yellow colored body ‘corpus luteum’.
- Withdrawal of hormones, essentially progesterone, leads to visible loss of endometrial tissue called as menstruation.
- Normal menstruation essentially is:
- Estrogen withdrawal bleeding
- Progesterone withdrawal bleeding
- Estrogen break-through bleeding
- Progesterone break-through bleeding
- The endometrial regeneration takes place from:
- Decidua functionalis
- Stratum compactum
- Stratum spongiosum
- Decidua basalis
- At the time of ovulation the endometrium is:
- 3 - 5 mm
- 7 - 8 mm
- About 10 mm
- > 10 mm
- In menstruation the following phase is fairly constant:
- Proliferative
- Secretory
- Both, proliferative and secretory
- None of the above
- Rise in the basal body temperature is seen:
- During the follicular phase
- Just before the ovulation
- Just after the ovulation
- Throughout the luteal phase
- Rise in the basal body temperature is:
- 0.5 – 1.0 °C
- >1.0 °C
- 0.5 - 1.0 °F
- >1.0 °F
- Each Spiral arteriole:
- Supplies large area in the endometrium
- Anastomoses with the adjacent spiral arteriole
- Is an end-arteriole
- None of the above
- Regeneration of the endometrium starts:
- Within two days
- After 2 days
- After 3 – 4 days
- After complete stoppage of bleeding
- In menstruation following prostaglandin has a major role to play:
- PGI2
- PGE2
- PGF2α
- PGF2β
- The primordial germ cell arises in:
- Foregut
- Yolk sac
- Amniotic sac
- Genital ridge
- Number of primordial follicles at birth are:
- 6 – 7 millions
- 2 millions
- 3,00,000
- 500
-
- Age of the patient
- Number of active primordial follicles in the residual pool
- Number of inactive primordial follicles in the pool
- Total number of follicles at birth
- The precursor for steroidogenesis is:
- Carbohydrates
- Proteins
- Cholesterol
- Arachidonic acid
- Aromatization of androgens takes place in:
- External thecal layer (theca externa)
- Internal thecal layer (theca interna)
- Granulosa layer
- None of the above
- Inhibin is synthesized by:
- Hypothalamus
- Pituitary
- Theca cells
- Granulosa cells
- Estrogen positive feedback operates on:
- Ovary
- Hypothalamus only
- Pituitary only
- Hypothalamus and pituitary both
- During ovulation breach in the capsule is caused by:
- Hyaluronidase
- Collagenase
- Phospholipase
- Protease
- Peak function of corpus luteum is seen:
- Immediately after ovulation
- At day 5 after ovulation
- Just before onset of degenerative changes
- None of the above
- Degeneration of corpus luteum is by:
- Lipoid degeneration
- Calcific degeneration
- Hyaline degeneration
- Fibrotic degeneration
- Metrorrhagia is:
- Regular bleeding at infrequent intervals
- Regular bleeding at frequent intervals
- Irregular bleeding at frequent intervals
- Irregular bleeding at infrequent intervals.
1 b | 2 d | 3 a | 4 b | 5 d | 6 c | 7 c | 8 a | 9 c | 10 b |
11 b | 12 b | 13 c | 14 c | 15 d | 16 d | 17 b | 18 d | 19 c | 20 c |
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