What causes irregular menstruation?

Reasons for Irregular Menstruation

Polycystic ovary syndrome (PCOS) is the single most common cause of irregular menstrual cycles, affecting approximately 4-6% of women in the general population, followed by functional hypothalamic amenorrhea (FHA), hyperprolactinemia, and thyroid dysfunction. 1

Primary Endocrine Causes

PCOS (Most Common)

• PCOS accounts for the majority of irregular menstrual cases and is characterized by elevated androgens, irregular or absent periods, and polycystic ovarian morphology on ultrasound. 1
• Laboratory findings typically show an LH:FSH ratio >2, which strongly suggests PCOS. 1
• The prevalence increases to 10-25% in women with temporal lobe epilepsy. 2
• PCOS is characterized by hyperandrogenic chronic anovulation with acceleration of pulsatile GnRH secretion. 2

Functional Hypothalamic Amenorrhea (FHA)

• FHA accounts for 20-35% of secondary amenorrhea cases and is caused by functional reduction in GnRH pulsatile secretion. 1
• Main contributing factors include stress and increased stress sensitivity, vigorous exercise patterns, weight loss and low BMI, psychological disorders, and caloric restriction or energy deficit. 2
• In athletes, FHA is part of the female athlete triad or Relative Energy Deficiency in Sport (RED-S). 2
• Laboratory findings include low/normal FSH and LH levels and negative progestin challenge test. 3

Hyperprolactinemia

• Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases, causing menstrual irregularities through elevated serum prolactin levels. 1
• Causes include pituitary adenomas, medications, hypothyroidism, and chronic renal failure. 2
• Clinical features may include galactorrhea. 3
• Prolactin levels >20 μg/L are considered abnormal, and pituitary MRI may be indicated if clinical features suggest hypothalamic-pituitary axis abnormality. 1

Thyroid Dysfunction

• Both hypothyroidism and hyperthyroidism can cause menstrual irregularities by affecting the hypothalamic-pituitary-ovarian axis. 1
• Altered thyroid hormone levels disrupt the hypothalamic-pituitary-ovarian axis. 2

Primary Ovarian Insufficiency (POI)

• POI is characterized by elevated FSH (>35 IU/L) and LH (>11 IU/L) levels. 1
• Patients can maintain unpredictable ovarian function and should not be presumed infertile. 1

Additional Medical Conditions

Chronic Liver Disease

• Advanced liver disease causes menstrual irregularities in >25% of women through altered estrogen metabolism and disruption of the hypothalamic-pituitary axis. 1

Medication-Induced Causes

• Oral contraceptives frequently induce irregular bleeding patterns, especially during the first three months of use. 1
• Delayed application or detachment of contraceptive patches for ≥48 hours can cause delayed periods and requires back-up contraception until a patch has been worn for 7 consecutive days. 1

Critical Diagnostic Pitfall: FHA-PCOM vs. True PCOS

This is the most commonly missed diagnosis that leads to inappropriate treatment:

• Approximately 40-47% of women with FHA have polycystic ovarian morphology (FHA-PCOM), which can be misdiagnosed as PCOS. 1
• This distinction is critical because FHA-PCOM requires correction of energy deficit as primary treatment, not PCOS-directed therapy. 1
• FHA-PCOM patients have higher BMI than FHA-non-PCOM patients, higher AMH and testosterone levels, higher LH response to GnRH test, and lower SHBG levels. 3
• Key differentiating features in FHA-PCOM include history of energy deficit (calorie restriction/dieting), low or normal BMI (lean body type), and absence of hyperandrogenic symptoms (no hirsutism, no hair loss). 3
• Laboratory features expected in FHA-PCOM include low estradiol levels with negative progestin challenge test, low or low-normal LH and FSH (not the elevated LH:FSH ratio seen in PCOS), and normal or only mildly elevated androgens. 3

Health Consequences of Irregular Menstruation

Bone Health

• Decreased bone mineral density and increased risk of osteoporosis are major complications of irregular menses, particularly in hypoestrogenic states. 1
• Patients with FHA are at particular risk for decreased bone density. 3

Cardiovascular and Metabolic Risk

• Women with menstrual disorders have a higher risk of developing hypertension and other cardiometabolic risk factors. 1
• Women with irregular menstrual cycles have 20% higher risk of developing heart disease and 17% higher risk of diabetes compared with those with regular menstrual cycles. 4

Diagnostic Approach

Initial Evaluation

• Pregnancy test should be the first step in evaluating irregular menstruation. 1
• Obtain menstrual chart for at least 6 months to document cycle patterns. 1

Laboratory Workup

• Initial workup should include serum FSH, LH, prolactin, and TSH levels. 1
• LH and FSH should be measured based on an average of three estimations taken 20 minutes apart between day 3 and 6 of the cycle. 1
• Progesterone measurement during mid-luteal phase can indicate anovulation, commonly caused by PCOS, FHA, or hyperprolactinemia. 1
• Additional testing may include androgen profile for suspected PCOS. 3
• Progestin challenge test can be used to determine estrogen status. 3

Imaging

• Pelvic ultrasound should be performed to evaluate for polycystic ovarian morphology and uterine abnormalities. 3

Clinical Red Flags

• Evaluate for eating disorders, excessive exercise, and psychological stressors in suspected FHA. 1
• Screen for obesity and truncal obesity, assessing menstrual regularity in cases of cycle disturbance. 1
• Look for hirsutism and check for galactorrhea, which may indicate hyperandrogenism requiring investigation. 1