Physiology of the Menstrual Cycle

Physiology of the Menstrual Cycle

• The menstrual cycle recurs every 21-35 days (mean 28 days)
• Blood flow lasts 3-7 days (mean 5 days)
• Average blood loss is 30-50 ml/cycle
• Initial cycles following menarche and those nearing menopause are typically irregular due to anovulation
• Women experience approximately 400 menstrual cycles between puberty and menopause
• Each cycle involves complex interactions between the hypothalamus, pituitary gland, ovaries, and endometrium

The Hypothalamus

• The hypothalamus is a small neural structure at the base of the brain above the optic chiasma
• It connects to the pituitary gland

Hypothalamic Releasing Hormones

• These are small peptides with short half-lives, degraded rapidly, and undetectable in serum
• They are released in minute quantities in a pulsatile manner
• They reach the anterior pituitary via the hypothalamic portal circulation
• Types of hypothalamic releasing hormones:
• Gonadotrophin-releasing hormone (GnRH): a decapeptide produced by the arcuate nucleus that stimulates synthesis and release of pituitary gonadotropins (FSH and LH)
• Thyrotropin-releasing hormone (TRH): stimulates the release of TSH
• Corticotrophin-releasing hormone (CRH): stimulates the release of ACTH
• Growth hormone-releasing hormone (GHRH): stimulates the release of GH
• Prolactin inhibiting factor (PIF or dopamine): inhibits production of prolactin (PRL)

The Pituitary Gland

• The pituitary gland lies at the base of the brain, below the hypothalamus within the sella turcica
• It has two major portions - the anterior and posterior pituitary glands

The Anterior Pituitary Gland (adenohypophysis)

• Derived from the ectoderm and indirectly connected to the hypothalamus through the hypophyseal-pituitary portal system
• This system is a major route for transporting hypothalamic releasing factors.

The Anterior Pituitary Gland Hormones

• The anterior pituitary produces six trophic hormones through five hormone-producing cell types:
• Follicle stimulating hormone (FSH) and Luteinizing hormone (LH) (gonadotrophins): Glycoproteins produced by Gonadotrophs and responsible for the growth, maturation, and rupture of Graafian follicles (ovulation), and maintenance of corpus luteum function
• TSH (Thyroid stimulating hormone): Produced by cells known as thyrotrophs
• ACTH (adreno-cortico-trophic hormone): Produced by Adrenocorticotrophs.
• GH (growth hormone): Produced by cells known as somatotrophs
• PRL: Produced by cells known as lactotrophs
• Pituitary hormones are stimulated and controlled by hypothalamic releasing hormones (GnRH, GHRH, TRH, and CRH)
• PRL is an exception, under chronic inhibition by prolactin inhibiting factor (PIF)
• When the pituitary stalk is damaged, it results in hypopituitarism for FSH, LH, GH, ACTH, and TSH
• Damage to the pituitary stalk is also associated with an increase in PRL secretion

The Posterior Pituitary Gland (neurohypophysis)

• The posterior pituitary transports oxytocin and vasopressin (antidiuretic hormone: ADH)
• They travel along neuronal axons from the supraoptic and paraventricular nuclei of the hypothalamus
• They are then released into circulation

The Ovarian Cycle

• A fetal ovary has 7 million primordial follicles at mid-gestation with the number declining sharply
• At birth, the number declines again to 1.5-2.0 million
• By poverty declines to 400,000
• Ovarian follicles gradually become exhausted until menopause
• The ovarian cycle includes the follicular phase, ovulation, and luteal phase

Follicular Phase

• Lasts from the first day of menses until ovulation (mean 14 days)
• Graafian follicles grow and mature under the influence of follicle stimulating hormone (FSH)
• They produce increasing amounts of E2, leading to proliferative changes in the endometrial glands

Primordial Follicle

• Each consists of a single oocyte, arrested in the diplotene stage of the pro-phase of the first meiotic division
• Consists of a single layer of flattened cells (granulosa cells) and cells of the ovarian stroma (theca cells)

Pre-Antral Follicle

• FSH stimulates growth of primordial follicles
• The oocytes grow and granulosa cells multiply to become a multilayered cuboidal shape, resulting in a preantral follicle

Two-Cell, Two-Gonadotrophin Hypothesis of Estrogen Production

• Within theca cells: LH stimulates the conversion of cholesterol to androstenedione, then transferred to granulosa cells
• Within granulosa cells: FSH stimulates aromatization of androgens into estrogens by the enzyme aromatase
• Estradiol (E2) is the chief ovarian estrogen, it enhances FSH receptors on granulosa cells and acts synergistically with FSH to increase LH receptors in the granulosa cells
• Androgens are produced within the theca cells
• At low levels, it enhances aromatization and increases estrogen production
• At high levels, it inhibits aromatization and produces follicular atresia

Control of Steroidogenesis

• Autocrine and paracrine mediators play an important role in folliculogenesis
• Inhibin: A peptide produced by granulosa cells that inhibits FSH production and enhances LH-induced androgen synthesis, thus the dominant follicle can continue development and other follicles undergo atresia
• Activin: A peptide produced by granulosa cells that augments FSH production
• Growth Factors: Insulin-like growth factor (IGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) help enhance the response to FSH

Selection of the Dominant Follicle

• During folliculogenesis a dominant follicle is selected to continue growth, maturation, and ovulation
• Other follicles will be arrested and later become atretic
• Characterized by a high number of FSH receptors in granulosa cells and the most efficient aromatase activity
• It contains the highest concentration of FSH induced LH receptors and the greatest amounts of E2 and inhibin produced

Preovulatory Follicle (Mature Graafian Follicle)

• The oocyte is pushed to one side of the follicle, and secretes a clear gelatinous material around it, forming the zona pellucida
• Simultaneously, the theca cells become differentiated into theca interna and theca externa around the multiple layered granulosa cells

Ovulation

• In the late follicular phase, FSH leads to increasing estradiol (E2) by the dominant follicle and induces LH receptors on granulosa cells
• High E2 levels exert a positive feedback effect on the pituitary gland which leads to release of LH rapidly and in increasing amounts to produce an LH surge
• Ovulation (oocyte release) happens approximately 36 hours after the onset of the LH surge and about 12 hours after the LH peak
• Resumption of meiosis occurs during the process of ovulation, with oocytes progressing from prophase I through metaphase II

The Luteal Phase

• Extends from the time of ovulation until menstruation and typically lasts for 14 days
• Corpus luteum (CL) formation: After ovulation, and under the influence of LH, the granulosa cells of the ruptured follicle undergoes luteinization to form CL
• Luteinized cells of the CL have a vacuolated appearance associated with the accumulation of a yellow pigment (lutein) which is where the CL name is derived from
• The CL produces copious progesterone (P), smaller amounts of (E2), and little inhibin which leads to decreased FSH & LH production, inhibiting new follicular growth in the luteal phase from starting
• Progesterone produced by the CL will lead to secretory changes in the endometrium, necessary for implantation of the embryo

Fate of the CL

• The luteal phase lasts about 14 days in most women
• The life span of the CL lasts around 9 days; then it undergoes luteolysis and becomes replaced by the avascular corpus albicans
• In absence of pregnancy the CL undergoes apoptosis and stops making progesterone (P) by 12-14 days after ovulation which releases gonadotrophin inhibition and FSH starts to rise
• In the presence of pregnancy, the trophoblastic production of human chorionic gonadotropins (hCG) will maintain (P) secretion from the CL until placental steroidogenesis is established about the 8th week of gestation
• As the CL dies, E2, P, and inhibin levels decline releasing the pituitary gland from the negative feedback effect of these hormones
• Subsequently, FSH levels begin to rise, and beginning a new ovarian and menstrual cycle

Feedback to the Hypothalamus

• The long feedback loop comes from ovarian hormones (estrogens and androgens)
• The short feedback loop comes from the pituitary hormones (FSH & LH)
• The ultra-short feedback loop comes from the hypothalamic releasing factors

Positive and Negative Feedback Loops

• E2 has an inhibiting effect on FSH (negative feedback), whereas high E2 levels stimulate LH production (positive feedback)
• Progesterone present in the mid-luteal phase has an inhibiting effect on LH (negative feedback) which consequently inhibits growth of primordial follicles in the luteal phase

The Endometrial Cycle

• Changes in the endometrium due to ovarian hormones throughout the menstrual cycle are divided into proliferative phase, secretory phase, and menstruation

The Proliferative Phase

• Coincides with the follicular phase of the ovarian cycle, and is characterized by both glandular and stromal growth
• Starts with the shedding of the endometrium at menstruation
• Continues under the effect of ovarian estrogen produced by the maturing follicles until ovulation occurs
• The epithelium lining the endometrial glands changes from a single layer of low columnar cells to pseudo-stratified epithelium with frequent mitoses, and the stromal component expands rapidly
• The endometrial thickness grows from 0.5 mm at the end of menstruation to about 8-12 mm at the end of the proliferative phase

The Secretory Phase

• Coincides with the luteal phase of the ovarian cycle, and features endometrial glandular secretory activity
• Begins shortly after ovulation, and continues under the effect of progesterone produced by the CL until menstruation starts
• Progesterone inhibits estrogen induced cellular proliferation, restricting the depth of endometrial thickness
• There is increase tortuosity of both glands and spiral arteries which allow structure to fit in the endometrial layer

Late Secretory Phase

• Progesterone induces irreversible maximum secretory effect (decidualization) of the stroma
• The surrounding stroma cells display increased mitotic activity and nuclear enlargement
• The three distinct zones of the endometrium include:
  • The basal portion (basalis): Represents the basal 25% of the endometrium, which is retained, shows few changes during the menstrual cycle.
  • The mid-portion (spongiosum): Composed of edematous stroma, glandular tortuosity and secretions
  • The superficial portion (compactum): Composed of decidualized stromal cells

Menstruation

• A Premenstrual sharp and rapid decline in Progesterone & Estradiol levels
• Results in coiling and vasoconstriction of the endometrial spiral arteries, with ischemia to the functional portion of the endometrium (superficial and intermediate layers)
• Vasoconstriction is initiated and controlled through the action of prostaglandin F2 alpha (PGF2-a), endothelin-1 (ET-1) and platelet-activating factor (PAF)
• Within 2 days from the onset of menstruation, the surface epithelium begins to regenerate under the influence of follicular phase estrogen

Cervical Mucus Changes During the Menstrual Cycle

• The physical and chemical properties of the cervical mucus vary in relation to the changing estrogen and progesterone levels in the follicular and luteal phases of the menstrual cycle
  • Follicular phase (estrogen effect): Profuse, decreased viscosity (thin-watery), decreased leucocytes, positive Ferning test (arborization test), positive Spinbarkeit test (Stretchability test) (threads 7-10 cm)
  • Luteal phase (progesterone effect): Scanty, increased viscosity (thick-viscid), increased leucocytes, negative Ferning test (arborization test), negative Spinbarkeit test (Stretchability test)
• Ferning test: Microscopic examination of a drop of cervical mucus left to dry for 10 minutes on a glass slide in the follicular phase will reveal an arborizing palm leaf pattern, due to its high sodium chloride and potassium content in response to a high estrogenic level (+ve test). In the luteal phase the arborizing pattern is lost giving a negative test
• Spinbarkeit test is positive when the cervical mucus can be drawn between two slides into threads stretching up to 10 cm due to high mucus content in response to high estrogen levels

Vaginal Epithelial Cellular Changes During the Menstrual Cycle

• Vaginal epithelium is composed of basal, intermediate, and superficial (mature) cells
• In the follicular phase, superficial cells predominate under estrogenic effect
• In the luteal phase, progesterone causes shedding of more intermediate cells
• Maturation index calculates the ratio of basal, intermediate, to superficial cells on vaginal cytology of the vaginal epithelium in different phases of the menstrual cycle
• Follicular phase vaginal cytology: Few lymphocytes, Maturation index 0-30-70
• Luteal phase vaginal cytology: Many lymphocytes, Maturation index 0-70-30

Dysmenorrhea

• Defined as pain and cramping during menstruation that interferes with normal activities and requires medication to control the symptoms
• Pain varies from mild discomfort to severe pain that causes patients to be bedridden for 1-3 days each month

Incidence of Dysmenorrhea

• Affects 45-90% of women in their reproductive age with variable degrees of severity
• Almost 50% of women will suffer significant pain
• 10% will become incapacitated during the first few days of their cycle

Classification of Dysmenorrhea

• Primary dysmenorrhea is idiopathic menstrual pain without identifiable pathology
• Secondary dysmenorrhea is painful menses due to underlying pathology (endometriosis, fibroids, adenomyosis, PID, cervical stenosis)

Primary Dysmenorrhea

• Almost always associated with ovulatory cycles, with no obvious organic cause
• Mostly results from increased levels of endometrial prostaglandins (PGLs)
• Condition improves after term pregnancies and deliveries

Diagnosis of Primary Dysmenorrhea

• Age: Commonly occurs in younger women < 20 years of age
• Pain: Occurs on the 1st or 2nd days of ovulatory cycle
• Associated symptoms: Nausea, vomiting, and headaches
• Physical examination: Reveals no obvious abnormalities or pelvic pathology
• Pelvic US: Reveals normal uterus, ovaries, and adnexa

Treatment of Primary Dysmenorrhea

• Non-steroidal anti-inflammatory drugs (NSAIDs): Taken at the onset of menses, continued for 1-3 days; used as needed
• Combined oral contraceptive pills (COCs): Used for cases that don't respond to NSAIDs or cannot tolerate side effects

Secondary Dysmenorrhea

• Might be present in both ovulatory and anovulatory cycles
• Symptoms happen because of an identifiable cause, like endometriosis, uterine leiomyomas, cervical stenosis, pelvic adhesions, and PID
• Pelvic US can diagnose smaller uterine myomas, ovarian endometriomas, and tuboovarian masses
• Laparoscopy is for diagnosing endometriosis, pelvic adhesions, and PID

Treatment of Secondary Dysmenorrhea

• Medical: NSAIDs to control the pain
• Hormonal: OCP, Gestagens, and GnRH agonists for endometriosis
• Surgical: For larger myomas, endometriomas, and tubo-ovarian mass

Premenstrual Syndrome (PMS)

• A group of physical and/or emotional changes that constantly occur and recur in the luteal phase of successive cycles
• It's severe enough to interfere with the patient's regular lifestyle
• Characteristics:
  • Symptoms that include headache, weight gain, bloating, breast tenderness, mood fluctuation, restlessness, irritability, anxiety, depression, and fatigue,
  • Symptoms have to be present 2 weeks to menstruation (luteal phase), with a 7-day symptom-free interval in the first half of the menstrual cycle
  • The highest incidence of PMS occurs in women in their late 20s to early 30s
• PMS is more pronounced in genetically and psychologically susceptible women
• Although women with PMS have normal levels of E2 & PRG, they may have an abnormal response to normal hormonal changes

Treatment of PMS

• Treatment is based on alleviating symptoms while considering the psychological aspects
• Selective serotonin reuptake inhibitors (SSRIs) helps to manage physical and emotional symptoms to with severe PMS and are taken as oral tablets throughout the menstrual cycle
• changes in lifestyle include regular exercise, balanced diet, reducing premenstrual stress, eliminating caffeine, cigarette smoking, and alcohol
• medications can slightly improve symptoms of PMS
  • calcium - 600 mg BID
  • Vitamin D - 800 IU/day
  • Vitamin B6 - 100 mg/day
  • Magnesium - 20 mg/day
• Oral Contraceptives help to reduce symptoms by reducing fluctuations in ovarian steroids