The menstrual cycle and menstrual cycle abnormalities

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), menstrual bleeding (menses) is regulated by hypothalamic and pituitary hormones. Even the smallest changes in hormone levels can result in menstrual cycle abnormalities. Hormonal changes are not necessarily pathological; they can be caused by a variety of conditions and factors (e.g., medication, stress). 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 abnormal uterine bleeding (AUB; e.g., increased frequency and/or 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 (PMS).

Hormonal feedback loops ^[1]

The menstrual cycle is a tightly regulated process in which the coordinated release of hormones from the hypothalamus, pituitary gland, and gonads produces a single mature oocyte. These hormones are controlled by positive and negative feedback loops.

• Follicular phase
  • 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 ovaries.
    • In the ovarian follicle, the theca cells and granulosa cells are in charge of hormone production.
  • LH stimulates theca cells and induces the production of progesterone and androstenedione.
  • FSH stimulates granulosa cells and recruits a group of maturing follicles in the ovary → production of estradiol and inhibin B in the growing follicles → negative feedback to the pituitary gland → inhibited FSH release
  • The day before the LH levels rise, one follicle becomes dominant (the remaining follicles regress as FSH levels decrease) and estradiol levels peak → positive feedback to the pituitary gland → LH levels increase rapidly
• Ovulation: LH surge induces ovulation → the mature oocyte is released from the dominant follicle and the corpus luteum produces progesterone → LH inhibition
• Luteal phase: falling LH levels cause degeneration of the corpus luteum → decreased progesterone and estradiol levels → the endometrium cannot be maintained → menstruation occurs

The hormonal feedback loop is also influenced by other hormones (e.g., prolactin) and neurotransmitters (e.g., opioids, acetylcholine, noradrenaline). The feedback mechanisms are controlled by upregulating or downregulating hormone production as needed.

Menstrual cycle ^[1][2]

• A normal menstrual cycle lasts 24–38 days (28 days on average), with the first day of menstrual bleeding counted as day 1 of the cycle. ^[3]
• Menses lasts an average of 3–7 days, with an average blood loss of 35–50 mL.
• The menstrual cycle involves simultaneous changes in the ovaries (ovarian cycle) and the uterus (uterine cycle).
• The cycles relate to one another
  • Ovarian changes are regulated by hormones released from the anterior pituitary gland.
  • Uterine cycle changes are regulated by hormones released from the ovary during the ovarian cycle.
    • Low estradiol levels keep FSH and LH levels low, leading to menstruation.
    • High estradiol levels lead to increased FSH and LH levels, causing thickening of the endometrium.
    • Estradiol and progesterone secreted by the corpus luteum allow for further development of the endometrium.
    • Estradiol and progesterone also inhibit secretion of FSH and LH, preventing other follicles from developing.
• The menstrual cycle changes with age.
  • First few years following menarche: irregular menstrual cycles (due to immaturity of the hypothalamic-pituitary-gonadal axis)
  • Menstrual cycles are longest at 25–30 years of age, with younger and older individuals having shorter cycles. ^[4]

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.

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) ^[5]
  • 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 ^[6]
  • 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 ^[5][7]

• 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

Primary amenorrhea ^[8][9]

• Definition: : the absence of menarche at 15 years of age despite normal development of secondary sexual characteristics, or absence of menses at 13 years of age in female individuals with no secondary sexual characteristics
• Etiology

• Clinical features: depend on the underlying cause
• Diagnostics
  • Pregnancy test
  • Check for secondary sexual characteristics and anatomical anomalies (physical examination, pelvic ultrasound).
    • Uterus absent: Perform karyotyping and serum testosterone to investigate for male/female genotype and androgen sensitivity.
    • Uterus present: Test FSH and LH levels.
      • Exclude imperforate hymen, vaginal atresia, and transverse vaginal septum.
      • ↑ FSH: primary ovarian insufficiency (e.g., Turner syndrome, Swyer syndrome, premature ovarian failure)
      • Normal or ↓ FSH: constitutional growth delay, hypogonadotropic hypogonadism
  • If galactorrhea is present: Check prolactin and TSH levels.
  • If symptoms of hyperandrogenism are present:
    • Check serum testosterone and dehydroepiandrosterone sulfate (DHEA-S).
    • If high: Suspect an androgen-secreting tumor.
  • If blood pressure is high: Suspect congenital adrenal hyperplasia.
• Treatment
  • Management of the underlying cause
    • Anatomical abnormalities: surgery
    • Hypogonadism: hormone replacement therapy with estrogens and progesterone
  • The goal of treatment is the progression of normal pubertal development.

Secondary amenorrhea

• Definition: the absence of menses for more than 3 months in individuals with previously regular cycles, or 6 months in individuals with previously irregular cycles
• Etiology
  • Pregnancy: most common cause of secondary amenorrhea
  • Ovarian disorders (e.g., premature ovarian failure, polycystic ovary syndrome )
  • Medications (antipsychotics, chemotherapy, oral contraceptives)
  • Hypothyroidism (↓ T3/T4 → ↑ TRH → ↑ prolactin → ↓ GnRH → ↓ estrogens)
  • Hyperthyroidism
  • Hyperprolactinemia
  • Sheehan syndrome
  • Asherman syndrome
  • Cushing syndrome
  • Adrenal insufficiency
  • Obesity
  • Hypergonadotropic hypogonadism
  • Hypogonadotropic hypogonadism
  • Functional hypothalamic amenorrhea: a dysfunction in the pulsatile secretion of GnRH
    • Etiology
      • Excessive exercise: e.g., in competitive athletes (also called exercise-induced amenorrhea)
      • Reduced calorie intake (e.g., in eating disorders like anorexia nervosa)
      • Stress
      • Female athlete triad syndrome: menstrual dysfunction, calorie deficit, and decreased bone density in athletic female young adults or adolescents
    • Pathophysiology: decreased leptin (low body fat) and/or increased cortisol (exercise/stress) → decreased pulsatile release of GnRH from the hypothalamus → decreased secretion of FSH and LH → decreased estrogen levels → anovulation and secondary amenorrhea → infertility
• Clinical features: depend on the underlying cause
• Diagnostics
  • Pregnancy test
  • If negative, obtain FSH, TSH, and prolactin levels.
    • ↑ FSH: ovarian insufficiency
    • ↑ TSH: hypothyroidism
    • ↑ Prolactin
      • Re-check history for medication intake (antipsychotics are the most frequent cause of medication-induced hyperprolactinemia).
      • Perform brain MRI to evaluate for pituitary adenoma.
  • Perform progestin challenge (10 days of progestin intake)
    • Withdrawal bleeding induced: anovulation (e.g., PCOS, idiopathic anovulation, premature ovarian failure)
    • No withdrawal bleeding (may indicate uterine anomalies or estrogen deficiency): test FSH levels.
      • ↑ FSH: hypergonadotropic hypogonadism or ovarian failure
      • ↓ FSH: combined estrogen and progesterone challenge
        • Withdrawal bleeding induced: hypogonadotropic hypogonadism
        • No withdrawal bleeding: endometrial or anatomical problem (e.g., Asherman syndrome)
    • If virilization is present: Check testosterone, DHEA-S, and 17-hydroxyprogesterone.
      • Mild elevation: PCOS, congenital adrenal hyperplasia, Cushing syndrome
      • Moderate-to-high elevation: androgen-producing tumor
• Treatment
  • Management of the underlying cause
    • Tumors
      • Surgical resection if possible
      • Prolactinoma: dopamine agonists (bromocriptine, cabergoline)
    • Functional hypothalamic amenorrhea
      • Lifestyle changes: reduce stress, improve nutrition, increase body weight (aim for BMI > 19 kg/m²)
      • Offer pulsatile GnRH therapy or gonadotropin therapy to induce ovulation. ^[8][9]
    • Premature ovarian failure: combined oral contraceptives (OCPs) or hormone replacement therapy
    • If trying to conceive:
      • Stimulation of ovulation with gonadotropin
      • If failed: assisted reproductive technology
    • Treatment goals: prevent complications (e.g., osteoporosis, heart disease) and maintain fertility

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

The female athlete triad of functional hypothalamic amenorrhea: low calorie intake/strenuous physical activity, low bone mineral density, and amenorrhea

Ovarian insufficiency

• Definition: failure of adequate ovarian function (endocrine as well as reproductive) before the age of 40, which often leads to premature menopause

Primary ovarian insufficiency (POI) ^[10]

• Definition: ovarian insufficiency despite adequate gonadotropin stimulation (previously called premature ovarian failure)
• Etiology ^[11]
  • Idiopathic (90% of cases)
  • Genetic disorders associated with ovarian hypoplasia, especially in women < 30 years; (e.g., Turner syndrome; , Swyer syndrome, androgen insensitivity syndrome, adrenogenital syndrome, fragile X syndrome)
  • Autoimmune diseases; (e.g., autoimmune lymphocytic oophoritis, Hashimoto thyroiditis, Addison disease, type I diabetes mellitus, pernicious anemia)
  • Toxins: Smoking is a major risk factor.
  • Iatrogenic: radiation and/or chemotherapy, prolonged GnRH agonist therapy, induction of multiple ovulation in infertility treatment
  • Infectious diseases (e.g., measles, mumps, tuberculosis of the genital tract)
• Pathophysiology: follicular dysfunction or depletion → ↓ estrogen levels → reduced feedback inhibition of estrogen on FSH and LH → ↑ FSH and LH (usually FSH > LH)
• Clinical features ^[12]
  • Climacteric symptoms such as vaginal dryness, night sweats, hot flashes, dyspareunia, and irritability
  • Abnormal/irregular bleeding pattern that can progress to secondary amenorrhea or permanent cessation of menstruation
  • Infertility or reduced fertility (Pregnancy is possible via in vitro fertilization.)
• Diagnostics
  • Confirmed by two ↑ FSH levels (> 30–40 mIU/mL) and two ↓ estradiol levels (< 50 pg/mL) at least 1 month apart after > 3 months of menstrual irregularities in a woman under age 40
  • Further tests help determine the underlying cause (e.g, karyotyping, thyroid function).
• Treatment
  • See “Hormone replacement therapy.”
  • Treatment of underlying causes

Secondary ovarian insufficiency

• Definition: ovarian insufficiency due to inadequate stimulation of the ovaries by the hypothalamus and/or pituitary
• See “Secondary hypogonadism.”

See also “Endometrial cancer.”

Definition

• Abnormal uterine bleeding (AUB; formerly known as dysfunctional 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.

Etiology ^[13]

• The International Federation of Gynecology and Obstetrics (FIGO) has developed a classification (the PALM-COEIN system) to distinguish between structural and nonstructural causes of abnormal uterine bleeding.
• Structural causes: polyps, adenomyosis, leiomyomas, and malignancy and hyperplasia (PALM)
• Nonstructural causes: coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, not otherwise classified (COEIN)

Types ^[1][14]

• Acute AUB: episodic uterine bleeding, in a nonpregnant female individual of reproductive age, that is of sufficient volume to require intervention to prevent further blood loss
• Chronic AUB: uterine bleeding of abnormal frequency, regularity, and/or volume that has persisted for > 6 months
• According to etiology
  • AUB-C: coagulopathies
  • AUB-O: ovulation disorders (e.g., disorders of the hypothalamic-pituitary axis, PCOS, obesity)
  • AUB-E: endometrial disorders
  • AUB-I: iatrogenic causes (e.g., estrogens, androgens, IUD)
  • AUB-N: not otherwise classified (e.g., uterine arteriovenous malformations, cesarean scar defect)

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.

Diagnostics of AUB

• Gynecological history
  • Age of menarche, last menstrual period, cycle length and regularity, pregnancies, family history, recent complaints
  • Evaluation of possible causes guided by the PALM-COEIN system
  • Characteristics of abnormal bleeding (frequency, regularity, duration, volume)
• Physical examination
  • If bleeding is acute: Ensure the hemodynamic stability of the patient.
  • Pelvic examination: Assess the severity and source of the bleeding (exclude structural abnormalities, neoplasms, and trauma).
  • Swabs for microbiologic testing: rule out cervicitis due to gonorrhea/chlamydial infection
• Pap smear: rules out cervical carcinoma
• Initial laboratory testing
  • CBC: rules out anemia
  • Platelet count, PT, PTT: rule out bleeding disorders
  • β-hCG: rules out pregnancy
  • Additional testing if required (e.g., thyroid function tests, prolactin, serum iron)
• Pelvic ultrasound ^[16]
  • Can be considered to rule out structural anomalies (e.g., leiomyoma, adnexal mass)
  • Allows for evaluation of endometrial thickness
• Endometrial biopsy: Indications vary by age group and the presence of risk factors.
  • Postmenopausal patients with any uterine bleeding and/or endometrial thickness ≥ 4 mm ^[16]
  • All patients > 45 years of age with frequent, heavy, and/or prolonged bleeding
  • Patients < 45 years of age with frequent, heavy, and/or prolonged bleeding who are at high risk for endometrial cancer (risk factors include obesity, polycystic ovary syndrome, type 2 diabetes, tamoxifen therapy, Lynch syndrome) and/or have failed medical management

Management of AUB

Nonsurgical management

• General measures: immediate supportive measures in hemodynamically unstable patients such as fluid resuscitation, blood transfusion, and intrauterine tamponade (e.g., intrauterine balloon, gauze packing)
• Pharmacological ^[17]
  • Acute AUB in a hemodynamically stable patient
    • High-dose IV conjugated equine estrogen
    • Alternatives: multi-dose regimens of OCPs or oral progestins, as well as tranexamic acid (second-line)
  • Ovulatory bleeding
    • OCPs, progestin (PO, IV, or as a levonorgestrel-releasing IUD)
    • NSAIDs (decrease blood loss)
    • Tranexamic acid
  • Anovulatory bleeding
    • Progestin PO for 10 days or as an IUD
    • OCPs

Surgical treatment ^[17]

• Indications
  • Severe bleeding/hemodynamic instability
  • Patient unresponsive to hormonal treatment
  • Hormonal treatment contraindicated (e.g., breast cancer, endometrial cancer)
  • Underlying medical condition requiring surgical repair
• Procedures
  • Uterine dilation and curettage (D&C) with concomitant hysteroscopy
    • Diagnostic and therapeutic
    • Used to identify intrauterine pathologies, take tissue samples, and remove the excess uterine lining
    • Can 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 the endometrium (e.g., with extreme cold, heat, radiofrequency energy)
    • Hysteroscopy prior to ablation may be useful for identifying and treating intrauterine structural abnormalities (e.g., polyps, fibroids).
    • Contraindications include:
      • Desire to have children: Endometrial ablation does not preserve fertility.
      • Pregnancy
      • Endometrial hyperplasia or endometrial cancer
      • History of transmyometrial uterine surgery
  • Transcatheter uterine artery embolization
    • Recommended in the case of fibroids
    • First-line therapy in patients with AUB due to uterine arteriovenous malformation (AVM)
  • Hysteroscopy: in case of endometrial polyps
  • Hysterectomy: reserved for patients who do not respond to any other treatment, no longer desire fertility, or have symptomatic anemia

In patients 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.

• Epidemiology
  • Occurs in up to 12% of female individuals ^[18]
  • Age of onset: 20–30 years of age ^[18]
• Clinical features ^[18][19]
  • Onset of symptoms 5 days before menstruation
  • Pain: dyspareunia, breast tenderness, headache, back pain, abdominal pain
  • Gastrointestinal changes: nausea, diarrhea, changes in appetite (food cravings)
  • Bloating and weight gain
  • Tendency to edema formation
  • Neurological: migraine, increased sensitivity to stimuli
  • Psychiatric: mood swings, drowsiness, lethargy, exhaustion, depression, anxiety, aggressiveness, social withdrawal
• Diagnostics ^[19]
  • Diagnosis is based on history and self-assessment (e.g., maintaining a PMS diary ).
  • Preexisting endocrine (e.g., thyroid disorders) and psychiatric (e.g., major depressive disorder) conditions should be ruled out.

• Treatment ^[19][20]
  • Lifestyle changes can be beneficial (e.g., regular exercise, healthy diet, avoiding individual triggers like alcohol, caffeine, or nicotine).
  • First-line treatment
    • NSAIDs (e.g., naproxen)
    • OCPs
    • SSRIs (e.g., fluoxetine) in the case of severe PMS and PMDD
  • Dietary supplements: reduce symptoms and improve mood swings
    • Calcium (1,200 mg/day) ^[19]
    • Vitamin E
    • Vitamin D
    • In the case of water retention/bloating:
      • Diuretics (e.g., spironolactone)
      • Magnesium

• Definition
  • Physiological preovulatory pain in female individuals of reproductive age
  • Also referred to as ovulatory or midcycle pain
• Epidemiology: occurs in approx. 40% of female individuals of reproductive age ^[21]
• Etiology: Enlargement and rupture of the follicular cyst and contraction of Fallopian tubes during midcycle ovulation lead to transient peritoneal irritation from follicular fluid. ^[1]
• Clinical features
  • Recurrent unilateral lower abdominal pain (can mimic appendicitis)
    • Pain occurs during midcycle in individuals with regular menses.
    • Dull and achy pain which can become cramp-like
    • Can last up to 3 days
  • Physical examination: lower abdominal pain on palpation, enlarged adnexa
• Diagnostics: Pelvic ultrasound shows simple follicular cyst and small amount of intraperitoneal fluid
• Management: reassurance; and symptomatic treatment with NSAIDs as needed

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