• Clinical science

The menstrual cycle and menstrual cycle abnormalities

Abstract

The menstrual cycle is a highly regulated, physiological process that makes conception and pregnancy possible. From the start of menstruation (menarche) to its cessation (menopause), monthly menstrual bleeding (menses) is regulated by hypothalamic and pituitary hormones. Even the smallest changes in hormone levels can result in menstrual cycle abnormalities. A variety of conditions and factors (e.g., medication, stress) can cause such hormonal changes, which are not necessarily pathological. Abnormal menstrual patterns are identified based on changes in the frequency, intensity, and onset of bleeding. Common manifestations of menstrual cycle abnormalities include amenorrhea (menstrual cessation), dysmenorrhea (painful menstruation), and menorrhagia (increased frequency and volume of menstruation). Discomfort prior to the onset of menstruation that is accompanied by psychiatric, gastrointestinal, and/or neurological symptoms is referred to as premenstrual syndrome.

Physiology of the menstrual cycle

Hormonal feedback loop

The menstrual cycle is a tightly regulated process that relies on the release of hormones from the hypothalamus, pituitary gland, and gonads in order to coordinate the release of a single mature oocyte.

  1. The hypothalamus releases gonadotropin-releasing hormone (GnRH) → stimulates anterior pituitary gland to release follicle-stimulating hormone (FSH)
  2. FSH recruits a group of maturing follicles in the ovary → growing follicles produce estradiol and inhibin A at increasing levels → negative feedback to the pituitary gland → inhibits the release of FSH
  3. One follicle becomes the dominant follicle and estradiol levels peak at the day before the luteinizing hormone (LH) surge → high levels of estradiol induce positive feedback to the pituitary gland LH levels increase
  4. LH surge induces ovulation → the mature oocyte is released from the dominant follicle and the corpus luteum produces progesterone → increase in progesterone inhibits LH surge
  5. Falling LH levels cause resolution of the corpus luteum → fall in progesterone and estradiol levels

The hormonal feedback loop is also influenced by other hormones (e.g., prolactin) and neurotransmitters (e.g., opioids, acetylcholine, noradrenaline).

Menstrual cycle

  • The cycle lasts 21–35 days on average, with the first day of menstrual bleeding counting as day 1 of the cycle.
  • The cycle consists of two phases:
  • The cycle changes with age:
    • First few years following menarche → irregular menstrual cycles (caused by immaturity of the hypothalamic-pituitary-gonadal axis)
    • Menstrual cycles are longest at 25–30 years of age, with younger and older women having shorter cycles.

Days 1–14

Ovaries: follicular phase

  1. FSH stimulates the development of several follicles in the ovariesgranulosa cells of follicles produce estrogen → suppresses release of FSH via a negative feedback loop
  2. Selection of a dominant follicle (Graafian follicle)
  3. High levels of estrogen trigger a positive feedback loop → release of FSH → subsequent LH surge initiates ovulation

Endometrium: desquamation and proliferative phase

Days 14–28

Ovaries: luteal phase

  1. Ovulation: rupture of Graafian follicleoocyte is released
  2. Following ovulation, the granulosa cells produce LH receptorsLH-induced transformation of the Graafian follicle into the corpus luteum → produces progesterone → inhibits LH release via a negative feedback loop
  3. If no pregnancy occurs → corpus luteum regresses

Endometrium: secretory phase

References:[1][2][3][4]

Menstrual pain and cycle abnormalities

Menstrual cycle abnormalities include changes in the frequency and intensity of menstruation as well as symptoms such as pronounced abdominal discomfort, gastrointestinal complaints, and/or psychiatric symptoms.

Dysmenorrhea (menstrual pain)

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)
  • Etiology: unknown; association with some risk factors (e.g., early menarche, nulliparity, smoking, obesity, positive family history)
  • Pathophysiology: increased endometrial prostaglandin (PGF2 alpha) production; vasoconstriction/ischemia and stronger, sustained uterine contractions
  • Clinical features
    • Spasmodic, crampy pain in the lower abdominal and/or pelvic midline (often radiating to the back or thighs)
    • Usually occurs during the first 1–3 days of menstruation
    • Headaches, diarrhea, fatigue, nausea, and flushing are common accompanying symptoms.
  • Diagnostics: Primary dysmenorrhea is a diagnosis of exclusion; conditions causing secondary dysmenorrhea must be ruled out.
  • 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

References:[5][6][3]

Amenorrhea (menstrual cessation)

Primary amenorrhea

Secondary amenorrhea

Physiological amenorrhea occurs before menarche, after menopause, during pregnancy, and during lactation.

References:[7][8][9][10][11][12]

Abnormal uterine bleeding (AUB)

Abnormal uterine bleeding is defined as menstrual bleeding that is abnormal and/or irregular in frequency, duration, and/or intensity. It may or may not be accompanied by dysmenorrhea.

Types and causes of AUB

  • The International Federation of Gynecology and Obstetrics (FIGO) has developed a classification (the PALM-COEIN system) to distinguish between structural and non-structural causes of abnormal intrauterine bleeding:
    • Structural causes: polyps, adenomyosis, leiomyomas, malignancy/hyperplasia (PALM)
    • Non-structural causes: coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, not yet classified (COEIN)
Description Common causes
Changes in overall cycle length Polymenorrhea
  • Cycles with intervals < 21 days
Oligomenorrhea
  • Cycles with intervals of 35–90 days
Changes in length and/or intensity of menses Hypermenorrhea
  • Heavy menstruation with bleeding volume > 150 mL (possibly visible blood clots)
Menorrhagia
  • Bleeding volume > 80 mL and/or length of menstruation > 7 days
Hypomenorrhea
  • Very low bleeding volume (< 25 ml)
Changes in timing of menses Metrorrhagia
  • Bleeding in between periods
Menometrorrhagia
  • Heavy and irregular bleeding
Spotting
  • Minimal bleeding seen in several conditions

Diagnostics

  1. Gynecological history
    • E.g., age at menarche, cycle length and regularity, pregnancies, family history, recent complaints
    • Evaluation of possible causes guided by the PALM-COEIN system
  2. Physical examination
    • If bleeding is acute, ensure the hemodynamic stability of the patient!
    • Assess the severity and source of bleeding → exclude structural abnormalities, neoplasms, and trauma
    • Pap smear → rules out cervical carcinoma
    • Swabs for microbiologic testing → rules out cervicitis due to gonorrhea/chlamydial infection
  3. Initial laboratory testing
  4. Ultrasound: rules out structural anomalies; (e.g., polycystic ovaries) and allows evaluation of endometrial thickness
  5. Endometrial biopsy indicated if:

Management

  1. General measures
    • Immediate supportive measures in hemodynamically unstable patients: fluid resuscitation, blood transfusion, and intrauterine tamponade (e.g., intrauterine balloon or gauze packing)
  2. Pharmacological
  3. Surgical treatment
    • Indications
      • Severe bleeding/patient hemodynamically unstable
      • Patient unresponsive to hormonal treatment
      • Hormonal treatment contraindicated (e.g., breast or endometrial cancer)
      • Underlying medical condition requiring surgical repair
    • Procedures
      • Dilation and uterine curettage (D&C) with concomitant hysteroscopy
        • Used to identify intrauterine pathologies, take tissue samples, remove excess uterine lining
        • May decrease bleeding in less than an hour
        • Preserves fertility
      • Endometrial ablation
        • Only indicated if other treatments have been ineffective or are contraindicated
        • Provides long-term improvement of uterine bleeding symptoms by destroying a thin layer of endometrium (e.g., with extreme cold, heat, or radiofrequency energy)
        • Hysteroscopy prior to ablation may be useful for identifying and treating intrauterine structural abnormalities (e.g., polyps or fibroids).
        • Does not preserve fertility
      • Transcatheter uterine artery embolization: first-line therapy in women with AUB due to uterine arteriovenous malformation (AVM)
      • Hysterectomy: reserved for women who do not respond to any other treatment

In girls with acute abnormal uterine bleeding and onset of menarche within the last year, anovulatory bleeding due to immaturity of the hypothalamic-pituitary-gonadal axis should be considered.

References:[7][13][3][8][14][15][16][17][4][18][19]

Premenstrual syndrome (PMS)

  • Definition: onset of severe discomfort or functional impairment prior to menstruation
  • Epidemiology: occurs in ∼ 5–10% of women
  • Clinical features
    • Onset of symptoms 5 days before menstruation; ; symptoms end within 4 days of start of menstruation
    • Pain: dyspareunia, breast tenderness, headache, back pain, abdominal pain
    • Gastrointestinal: nausea, diarrhea, changes in appetite
    • Tendency to edema formation
    • Neurological: migraine, increased sensitivity to stimuli
    • Psychiatric: mood swings, drowsiness, lethargy, exhaustion, depression, anxiety, aggressiveness
    • Premenstrual dysphoric disorder (PMDD): severe form of affective symptoms that interferes with daily life, including having abnormal disagreements with family, friends, and colleagues
  • Diagnostics
    • Diagnosis is based on history and self-assessment (e.g., by maintaining a PMS diary )
    • Preexisting endocrine (e.g., thyroid disorders) and psychiatric (e.g., major depressive disorder) conditions should be ruled out.
  • Treatment

References:[20][21][22][23]

Mittelschmerz

  • Epidemiology: occurs in ovulating women
  • Cause: : Enlargement and rupture of the follicular cyst during ovulation midcycle leads to transient peritoneal irritation (“midcycle pain”).
  • Clinical features: recurrent, unilateral, lower abdominal pain
  • Management: symptomatic treatment with NSAIDs as needed

References:[4]

Differential diagnosis and treatment of dysmenorrhea and menorrhagia

Primary dysmenorrhea Endometriosis Adenomyosis Endometritis Endometrial hyperplasia/carcinoma Uterine leiomyoma
Etiology/risk factors
  • ↑ PGF2alpha production → vasoconstriction/ischemia and stronger, sustained uterine contractions
  • Retrograde menstruation
  • Endometrial hyperplasia: abnormal proliferation of endometrial glands due to estrogen stimulation and insufficient opposing progestin stimulation → increases risk for endometrial cancer
  • The most important risk factor is increased and/or unopposed estrogen activity (e.g., caused by estrogen monotherapy, obesity, or an immature hypothalamic-pituitary-gonadal axis.
Clinical features
  • Spasmodic, crampy pain in the lower abdominal and/or pelvic midline
Diagnostics
  • Diagnosis of exclusion
  • MRI and ultrasound can support the diagnosis and/or assist in ruling out other diagnoses (particularly leiomyoma)
  • Histopathology (only method allowing definitive diagnosis)
  • Physical examination
  • Testing for typical pathogens (e.g., chlamydia)
  • Endometrial biopsy (to evaluate chronic endometritis that is unrelated to pregnancy)
  • Ultrasound (best initial test)
  • MRI to evaluate surgical options and differential diagnoses
Treatment
  • Pharmacologic
  • Surgical
    • Conservative: excision, cauterization, and ablation of lesions; removal of adhesions
    • Definitive: total abdominal hysterectomy (TAH)/bilateral salpingo-oophorectomy (BSO)
  • Pharmacologic
  • Surgical
    • Conservative: hysteroscopyendometrial ablation/resection
    • Definitive: hysterectomy
  • Surgical
    • Total hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO)
    • Additional advanced radical hysterectomy and removal of the upper vagina (according to Wertheim-Meigs)
  • Medical
  • Treat only if symptomatic
  • Pharmacologic
    • GnRH agonists, progestins, levonorgestrel-releasing IUD
    • NSAIDs
    • Antifibrinolytics
    • Androgenic agonists (e.g., danazol)

References:[7][13][24]