The menstrual cycle

The menstrual cycle is a highly regulated physiological process required for conception and pregnancy. From the start of menstruation (menarche) to its cessation (menopause), menstrual bleeding (menstruation) is regulated by the coordinated release of hormones from the hypothalamus, pituitary gland, and ovaries. These hormones trigger simultaneous changes in the ovaries (ovarian cycle) and the uterus (uterine cycle). Mittelschmerz is a physiological condition experienced by some individuals characterized by unilateral lower abdominal pain during ovulation; it may be initially misdiagnosed as appendicitis, ectopic pregnancy, or ovarian torsion in individuals who present with acute pelvic pain or acute abdomen. Management involves reassurance and nonopioid analgesics.

Menstrual cycle abnormalities include changes in the frequency and intensity of menstruation as well as symptoms such as pronounced abdominal discomfort, gastrointestinal issues, and psychiatric symptoms. Amenorrhea, abnormal uterine bleeding, and premenstrual disorders are discussed separately.

Menstrual cycle

• The menstrual cycle is a highly regulated physiological process in which the coordinated release of hormones from the hypothalamus, pituitary gland, and ovaries produces a mature oocyte and prepares the endometrium for blastocyst implantation.
• Average cycle duration: 28 days (24–38 days)
• First day of menstruation: day 1 of the cycle
• Average duration of menstruation: 5 days ^[3]
• Average blood loss: 35–50 mL
• Simultaneous changes in the ovaries (ovarian cycle) and the uterus (uterine cycle)
  • Ovarian cycle: 3 phases, regulated by hormones released from the hypothalamus and pituitary gland
    • Follicular phase: production and maturation of a dominant follicle
    • Ovulation: release of the oocyte from the dominant follicle
    • Luteal phase: formation and degeneration of the corpus luteum
  • Uterine cycle: 3 phases, regulated by hormones released from the ovary during the ovarian cycle
    • Menstrual phase: endometrial desquamation
    • Proliferative phase: regeneration of the functional layer of the endometrium
    • Secretory phase: endometrial differentiation in preparation for possible blastocyst implantation

Ovarian and uterine changes during the menstrual cycle

• Follicular phase (approx. day 1–14) ; ^[4]
  • The hypothalamus releases gonadotropin-releasing hormone (GnRH) in pulses, stimulating the anterior pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
  • FSH and LH stimulate the growth of a cohort of antral follicles.
  • LH stimulates ovarian theca cells and induces the production of progesterone and androstenedione (substrates for estradiol synthesis in granulosa cells).
  • FSH stimulates ovarian granulosa cells, which produce estradiol and inhibin.
  • Estradiol and inhibin block the release of gonadotropins (negative feedback).
  • Decreasing FSH levels lead to a regression of all follicles except one dominant follicle, which continues to develop despite falling FSH levels. ^[5]
  • The dominant follicle produces high levels of estradiol, which leads to a switch from negative to positive feedback in the hypothalamus and pituitary gland, resulting in a rapid increase in gonadotropin levels (LH surge). ^[6]
• Ovulation (approx. day 14): LH surge induces the release of the mature oocyte from the dominant follicle.
• Luteal phase (for 14 days after ovulation) ; :
  • The ruptured follicle transforms into the corpus luteum, primarily producing progesterone and some estradiol.
  • Progesterone and estradiol inhibit gonadotropin release (switch back to negative feedback).
  • In the absence of fertilization, falling LH levels lead to degeneration of the corpus luteum.
  • Discontinuation of progesterone and estradiol production by the corpus luteum results in cessation of gonadotropin inhibition, initiating the follicular phase.

• Menstrual phase (day 1 to approx. day 5)
  • In the absence of fertilization, the corpus luteum degenerates.
  • Decreasing progesterone and estradiol levels induce vasospasms and ischemia in the uterine spiral arteries and apoptosis of the functional layer of the endometrium. ^[7][8][9]
  • These changes lead to shedding of the endometrial lining, which manifests as menstruation.
• Proliferative phase of the menstrual cycle (approx. day 5–14): Estradiol produced by the growing follicles promotes endometrial proliferation.
  • Uterine spiral arteries regenerate and extend two-thirds of the way into the endometrium.
  • Stromal cells divide, enlarge, and accumulate glycogen.
  • Endometrial glands become straight, tubular, and lined by simple columnar epithelium.
  • Endometrial epithelial cells proliferate (cells have high mitotic activity).
• Secretory phase (approx. day 14–28): Progesterone from the corpus luteum promotes endometrial differentiation and other changes that prepare the body for blastocyst implantation.
  • Stromal cells become edematous and uterine spiral arteries extend the full length of the endometrium.
  • Endometrial glands increase tortuosity and production of glycogen-rich secretions.
  • Basal body temperature increases.
  • Cervical mucus secretion increases, which protects the uterus from foreign substances and cells (e.g., sperm).

• First few years after menarche: irregular menstrual cycles (due to immaturity of the hypothalamic-pituitary-gonadal axis)
• 25–30 years of age: Menstrual cycles are longest.
• Perimenopause: irregular menstrual cycles (due to fluctuating hormone levels)

Mittelschmerz (also known as midcycle pain or ovulatory pain) is physiological pain experienced by some individuals during ovulation. ^[10][11]

Epidemiology

Mittelschmerz occurs at least once in > 50% of premenopausal individuals. ^[12]

Etiology ^[12]

• Unclear
• Proposed etiologies include:
  • Enlargement and rupture of the follicular cyst
  • Spasms of the fallopian tubes or uterus
  • Transient peritoneal irritation from follicular fluid or blood

Clinical features

• Unilateral lower abdominal pain (often recurrent) ^[12][13]
  • Pain occurs mid-cycle (days 14–16 of the menstrual cycle) in individuals with regular cycles.
  • Usually located in the iliac fossa but may be generalized ^[13][14]
  • Can last from minutes up to 48 hours ^[10][14]
  • May be accompanied by ovulation bleeding: light bleeding or blood-stained discharge during the midpoint of the menstrual cycle ^[15]
• Physical examination
  • Lower abdominal pain on palpation ^[16]
  • Possible referred pain and rebound tenderness ^[16]
  • Adnexal tenderness or, rarely, a mass ^[14][17]

Diagnostics

• Clinical diagnosis ^[11][12]
• If there is diagnostic uncertainty, consider laboratory studies or imaging to rule out differential diagnoses of acute abdomen. ^[12][16]
• Pelvic ultrasound (if performed) may show signs of ovulation, e.g.: ^[18]
  • A small amount of intraperitoneal fluid
  • Increased echogenicity in ovarian follicles

It may be difficult to distinguish between symptoms of mittelschmerz and those of acute appendicitis or other adnexal emergencies. ^[12][16]

Management

• Reassurance and ; nonopioid analgesics (e.g., NSAIDs) as needed ^[11][13]
• For recurrent episodes, consider hormonal contraception to suppress ovulation. ^[19]

Abnormal menstrual patterns include changes in the frequency, intensity, and/or onset of bleeding. Common manifestations of menstrual cycle abnormalities include:

• Dysmenorrhea (painful menstruation)
• Amenorrhea (absence of menstruation)
• Abnormal uterine bleeding (e.g., increased frequency and/or volume of menstruation)
• Premenstrual disorders (cyclical physical, psychological, and behavioral changes before menstruation)

Primary dysmenorrhea

• Definition: recurrent lower abdominal pain shortly before or during menstruation (in the absence of pathologic findings that could account for those symptoms)
• Epidemiology
  • Prevalence up to 90% (most common gynecologic condition) ^[20]
  • Manifests during adolescence (typically within three years of menarche)
• Etiology
  • The etiology of primary dysmenorrhea is not completely understood.
  • Associated with some risk factors (e.g., early menarche, nulliparity, smoking, obesity, positive family history)
• Pathophysiology: increased endometrial prostaglandin (PGF2 alpha) production leads to vasoconstriction/ischemia and stronger, sustained uterine contractions (to prevent blood loss).
• Clinical features ^[21]
  • Usually occurs during the first 1–3 days of menstruation
  • Spasmodic, crampy pain in the lower abdominal and/or pelvic midline (often radiating to the back or thighs)
  • Headaches, diarrhea, fatigue, nausea, and flushing are common accompanying symptoms.
  • Normal pelvic examination
• Diagnostics
  • Primary dysmenorrhea is a diagnosis of exclusion.
  • Rule out conditions that cause secondary dysmenorrhea (e.g., endometriosis).
• Treatment
  • Symptomatic treatment: pain relief (e.g., NSAIDs), topical application of heat
  • Hormonal contraceptives (e.g., combined oral contraceptive pill, IUD with progestogen)

Secondary dysmenorrhea ^[20][22]

• Definition: recurrent lower abdominal pain shortly before or during menstruation that is due to an underlying condition
• Epidemiology
  • May begin later in life than primary dysmenorrhea
  • Commonly affects female individuals ≥ 25 years of age.
• Etiology
  • Uterine causes
    • Pelvic inflammatory disease (PID)
    • Intrauterine device (IUD)
    • Adenomyosis
    • Fibroids (intracavitary or intramural)
    • Cervical polyps
  • Extrauterine causes
    • Endometriosis
    • Adhesions
    • Functional ovarian cysts
    • Inflammatory bowel disease
• Clinical features
  • Depend on the underlying cause
  • Secondary dysmenorrhea should be suspected in the following cases:
    • Onset: after 25 years of age
    • Abnormal pelvic examination (e.g., uterine size, cervical motion tenderness, adnexal tenderness, masses, vaginal/cervical discharge)
    • The pain tends to get worse over time.
    • No previous history of pain with menstruation
    • Infertility (e.g., adhesions, endometriosis, PID)
    • Irregular cycles
    • Abnormal uterine bleeding (e.g., adenomyosis, fibroids, polyps)
    • Dyspareunia or postcoital bleeding
    • Partial or no response to therapy with NSAIDs and/or hormonal contraceptives
• Diagnostics
  • Depend on the underlying cause
  • Initial laboratory testing
    • CBC with differential (rules out infection)
    • Urinalysis (rules out UTIs)
  • Other
    • β-hCG (rules out ectopic pregnancy),
    • Gonococcal/chlamydial swabs (rule out STDs and PID)
  • Pelvic ultrasound
• Treatment: depends on the underlying cause

• A syndrome characterized by any one of the following in nonpregnant individuals of reproductive age:
  • Abnormal frequency, duration, regularity, and/or volume of menstruation
  • Intermenstrual bleeding
  • Unscheduled bleeding
• See “Abnormal uterine bleeding” for details.

The most common causes of abnormal uterine bleeding (AUB) can be remembered by using the PALM-COEIN system: Polyps, Adenomyosis, Leiomyomas, Malignancy and hyperplasia, Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, Not otherwise classified.

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