What are the potential causes of irregular periods in a 28-year-old female with previously regular menstrual cycles?

Irregular Periods in a 28-Year-Old Female with Previously Regular Cycles

The most common cause of new-onset irregular periods in a 28-year-old with previously regular cycles is polycystic ovary syndrome (PCOS), which affects 4-6% of women and should be your primary diagnostic consideration, followed by functional hypothalamic amenorrhea (FHA), hyperprolactinemia, and thyroid dysfunction. 1

Initial Diagnostic Approach

First, exclude pregnancy with a urine or serum pregnancy test—this is mandatory before proceeding with any further evaluation. 2

After excluding pregnancy, obtain a detailed menstrual history documenting:

• Exact cycle lengths over the past 6 months (oligomenorrhea is defined as cycles >35 days, polymenorrhea as <23 days) 3
• Pattern of bleeding (heavy, light, spotting, or absent) 3
• Any recent weight changes, stress levels, or changes in exercise patterns 1

Primary Causes to Investigate

Polycystic Ovary Syndrome (PCOS)

PCOS is the single most common endocrine cause of irregular cycles and should be investigated first in this age group. 1

Look for associated features:

• Hirsutism (male-pattern hair growth) 3
• Acne or oily skin 4
• Weight gain or obesity (BMI >25) 3
• Truncal obesity (waist-to-hip ratio >0.9) 3

Order initial labs (drawn on cycle days 3-6 if possible):

• LH and FSH levels (calculate based on average of three measurements taken 20 minutes apart): LH/FSH ratio >2 strongly suggests PCOS 3, 1
• Total testosterone (>2.5 nmol/L is abnormal) 3
• Androstenedione (>10.0 nmol/L suggests PCOS or adrenal hyperplasia) 3

Obtain pelvic ultrasound to assess for polycystic ovarian morphology (multiple peripherally arranged follicles 2-5mm in diameter). 3, 4

Functional Hypothalamic Amenorrhea (FHA)

FHA accounts for 20-35% of secondary amenorrhea cases and is caused by stress, excessive exercise, or inadequate caloric intake. 1, 5

Assess for:

• Recent psychological stressors or major life changes 1
• Exercise patterns (>10 hours/week of intense training warrants evaluation) 2
• Eating patterns, restrictive dieting, or weight loss history 2
• Calculate energy availability: is the patient consuming >30 kcal/kg fat-free mass/day? 1

Critical diagnostic pitfall: Approximately 40-47% of women with FHA have polycystic ovarian morphology on ultrasound (FHA-PCOM), which can be misdiagnosed as PCOS. 1 The distinction is critical because FHA-PCOM requires correction of energy deficit as primary treatment, not PCOS-directed therapy. 1

Key differentiating features:

• FHA typically shows LH/FSH ratio <1 (in 82% of cases), while PCOS shows ratio >2 2
• FHA shows low estradiol (<30 pg/mL) and thin endometrium (<5mm on ultrasound) 2
• Mid-luteal progesterone <6 nmol/L indicates anovulation, common in both conditions 3

Hyperprolactinemia

Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases. 1, 5

Screen for:

• Galactorrhea (nipple discharge or crusting) 3
• Visual changes or headaches (suggesting pituitary tumor) 2
• Medications that can elevate prolactin (antipsychotics, metoclopramide) 3

Order morning resting prolactin level (not post-stress or post-exercise):

• Levels >20 μg/L are abnormal 3, 1
• If elevated, rule out hypothyroidism and consider pituitary MRI 3, 1

Thyroid Dysfunction

Both hypothyroidism and hyperthyroidism disrupt the hypothalamic-pituitary-ovarian axis and cause menstrual irregularities. 1, 5

Order TSH as part of initial workup for all patients with new irregular cycles. 2

Medication-Induced Causes

If the patient recently started hormonal contraceptives, irregular bleeding is common during the first three months and is generally not harmful. 3, 6

Review all medications, particularly:

• Oral contraceptives (breakthrough bleeding expected in first 3 months) 6
• Contraceptive implants (22% develop amenorrhea, 34% have infrequent spotting) 3
• Anticonvulsants (certain agents lower contraceptive effectiveness and may affect cycles) 3, 6
• Antidepressants (potential drug interactions with hormonal regulation) 3

Standard Laboratory Panel

Order the following tests for all patients with new irregular cycles:

• Pregnancy test (urine or serum β-hCG) 2
• TSH 2
• Prolactin (morning, resting) 3, 2
• LH and FSH (days 3-6 of cycle, average of three measurements 20 minutes apart) 3, 2
• Total testosterone 3
• Mid-luteal progesterone (to confirm ovulation if cycles resume) 2

Red Flags Requiring Urgent Evaluation

Evaluate immediately for:

• Significant unintentional weight loss or signs of eating disorder (requires multidisciplinary team) 2
• Galactorrhea with headaches or visual changes (pituitary pathology) 2
• Heavy or prolonged bleeding (rule out endometrial pathology, fibroids, or malignancy) 3
• Signs of virilization beyond simple hirsutism (suggests androgen-secreting tumor) 3

Long-Term Health Implications

Irregular cycles are not benign—they indicate anovulation and carry significant health risks:

• Decreased bone mineral density and increased osteoporosis risk (particularly in hypoestrogenic states like FHA) 1, 5
• Increased cardiovascular risk (women with menstrual disorders have higher rates of hypertension) 1
• Endometrial hyperplasia risk from unopposed estrogen in anovulatory PCOS 3
• Infertility from chronic anovulation 3

If amenorrhea persists >6 months, obtain DXA scan for bone mineral density assessment regardless of age, as prolonged hypoestrogenic states significantly increase osteoporosis risk. 2, 5

Common Pitfalls to Avoid

• Do not assume irregular cycles in a stressed or athletic woman are benign—other pathology must be excluded even when clinical picture suggests FHA. 2
• Do not prescribe oral contraceptives as first-line therapy without establishing diagnosis—this masks the problem without addressing underlying causes and provides false reassurance. 2
• Do not overlook eating disorders—patients frequently minimize symptoms, requiring direct questioning about specific behaviors. 2
• Do not miss the FHA-PCOM vs. true PCOS distinction—treatment approaches are fundamentally different. 1
• Do not delay bone density assessment if amenorrhea extends beyond 6 months. 2