What is the appropriate workup and treatment for a female patient of reproductive age presenting with irregular periods?

Workup and Treatment for Irregular Periods in Reproductive-Age Women

For a reproductive-age woman presenting with irregular periods, begin by excluding pregnancy with beta-hCG testing, then measure TSH and prolactin to identify reversible causes, followed by hormonal evaluation (FSH, LH, testosterone, progesterone) and transvaginal ultrasound to assess for structural abnormalities and polycystic ovary syndrome (PCOS). 1

Initial Diagnostic Workup

Mandatory First-Line Tests

• Pregnancy test (beta-hCG) must be performed first in all reproductive-age women with menstrual irregularities 1
• TSH and prolactin levels should be measured to identify thyroid disease and hyperprolactinemia as reversible causes of ovulatory dysfunction 1
• Transvaginal ultrasound is essential to assess endometrial thickness and exclude structural abnormalities such as polyps, fibroids, or adenomyosis 1, 2

Hormonal Evaluation

The timing of blood draws is critical for accurate interpretation:

• FSH and LH: Measure between cycle days 3-6 (or randomly if amenorrheic), ideally averaging three samples taken 20 minutes apart 3

  • LH/FSH ratio >2 suggests PCOS
  • FSH >35 IU/L suggests premature ovarian insufficiency
  • LH <7 IU/mL may indicate hypothalamic dysfunction 3

• Progesterone: Measure during mid-luteal phase (approximately day 21 of a 28-day cycle) 3

  • Levels <6 nmol/L indicate anovulation 3
  • Common causes of anovulation include PCOS, hypothalamic amenorrhea, and hyperprolactinemia 3

• Testosterone and androgens: Measure on cycle days 3-6 3

  • Testosterone >2.5 nmol/L suggests hyperandrogenism 3
  • Consider DHEAS (>3800 ng/mL in women aged 20-29) to rule out adrenal pathology 3
  • Androstenedione >10.0 nmol/L warrants evaluation for adrenal or ovarian tumors 3

• Fasting glucose and insulin: Assess for insulin resistance, particularly if PCOS is suspected 3

  • Fasting glucose >7.8 mmol/L suggests diabetes
  • Glucose/insulin ratio >4 indicates reduced insulin sensitivity 3

Important Caveats

• Do not measure prolactin post-ictally in women with epilepsy, as levels may be falsely elevated 3
• Discontinue hormonal contraceptives at least 2 months before hormonal evaluation when assessing for premature ovarian insufficiency 3
• Measure FSH and estradiol randomly if amenorrheic, or during early follicular phase (days 2-5) if oligomenorrheic 3

Evaluation for Specific Conditions

PCOS Assessment

PCOS affects 4-6% of the general population but is the most common cause of irregular periods in reproductive-age women 3, 4:

• Clinical criteria: Oligomenorrhea/amenorrhea, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound 3
• Ultrasound findings: >10 peripheral cysts (2-8 mm diameter) in one plane with thickening of ovarian stroma 3
• Note: Isolated polycystic ovaries (17-22% of women) without symptoms should not be confused with PCOS 3
• Menstrual pattern: Cycles of 35-60 days are most common in community populations, while cycles >60 days are more common in hospital populations 4

Structural Pathology Exclusion

Before initiating hormonal treatment, structural causes must be ruled out 5, 1:

• Transvaginal ultrasound is the primary screening method 2
• Saline infusion sonohysterography is more accurate for detecting endometrial polyps and submucous leiomyomas 2
• Hysteroscopy with biopsy remains the reference standard for definitive diagnosis of intracavitary lesions 2

Treatment Approach

First-Line Medical Management

Combined hormonal contraceptives (CHCs) are the recommended first-line treatment for ovulatory dysfunction bleeding in women who need contraception or can tolerate estrogen. 5, 1

• ACOG recommends CHCs as a medical treatment option for abnormal uterine bleeding associated with ovulatory dysfunction 5
• Any standard CHC formulation can be used based on patient preference and medical eligibility, as all work through the same mechanism of endometrial stabilization 5
• Verify no contraindications using the U.S. Medical Eligibility Criteria for Contraceptive Use before prescribing 5
• CHCs are particularly appropriate when contraception is desired 5

Alternative Hormonal Options

For women who cannot use estrogen-containing products:

• Cyclic progestin therapy is an alternative for women who do not require contraception or have contraindications to CHCs 5, 1
• Progesterone capsules 400 mg daily for 10 days can be used for secondary amenorrhea 6
• Progesterone capsules 200 mg daily for 12 continuous days per 28-day cycle when used with estrogen for endometrial protection 6
• Progestin-only contraception is recommended by the American Academy of Family Physicians as an alternative option 1

Important warning: Progesterone capsules contain peanut oil and should not be used in patients with peanut allergy 6

Adjunctive Therapies for Bleeding Control

• NSAIDs (5-7 days) can reduce bleeding irregularities and improve endometrial blood flow 3, 1
  • Celecoxib 200 mg daily for 5 days or mefenamic acid 500 mg three times daily for 5 days have shown efficacy 3
• Short-term estrogen therapy (10-20 days) can be considered for acute bleeding episodes if medically eligible 3

Monitoring and Follow-Up

• Reassess at 3-6 months to evaluate treatment response, menstrual pattern normalization, and patient satisfaction 1
• If irregular bleeding persists and is unacceptable to the patient, counsel on alternative methods and offer another option 3, 1

When to Refer or Investigate Further

Referral Indications

• No signs of puberty by age 13 or primary amenorrhea by age 16 warrants referral to pediatric endocrinology/gynecology 3
• Menstrual cycle dysfunction suggesting premature ovarian insufficiency in post-pubertal survivors of gonadotoxic treatment requires referral to gynecology/reproductive medicine/endocrinology 3
• Failure of medical management necessitates further investigation 1

Additional Investigation When Treatment Fails

• Hysteroscopy to visualize the endometrial cavity and diagnose focal lesions that may have been missed 1
• Saline infusion sonohysterography or MRI for better structural evaluation 1
• Consider underlying bleeding disorders if there is flooding (changing pad/tampon more than hourly), clots ≥1 inch diameter, or personal/family history of bleeding 7

Common Pitfalls to Avoid

• Do not assume all irregular bleeding is benign: Always exclude pregnancy, structural pathology, and endometrial disease before initiating treatment 5, 1
• Do not use cyclic progestins as first-line for ovulatory dysfunction: They do not significantly reduce menstrual bleeding in women who ovulate 8
• Do not forget to assess for systemic causes: Thyroid disease, hyperprolactinemia, and coagulopathies can present as irregular periods 1, 7
• Do not overlook PCOS complications: Women with cycles >60 days have increased rates of spontaneous abortion and endometrial hyperplasia 4
• Be aware of progesterone capsule side effects: Some women experience extreme dizziness, drowsiness, blurred vision, or difficulty walking; advise taking at bedtime in standing position with water 6