What are the causes and treatment options for irregular periods in a 26-year-old female?

Causes of Irregular Periods at Age 26

The most common causes of irregular periods in a 26-year-old woman are polycystic ovary syndrome (PCOS), thyroid dysfunction (particularly hypothyroidism), hyperprolactinemia, and stress-related hypothalamic dysfunction, with PCOS affecting 4-6% of reproductive-age women and being the leading endocrine cause. 1, 2

Primary Diagnostic Evaluation

First-line mandatory testing includes:

• Pregnancy test (beta-hCG) - Must be obtained regardless of reported contraceptive use to rule out pregnancy as the cause 1, 3
• Thyroid function tests (TSH and free T4) - Hypothyroidism is one of the most common endocrine causes, with target TSH 0.4-4.5 mIU/L 1, 3
• Prolactin level - Hyperprolactinemia frequently causes menstrual irregularity and can be secondary to hypothyroidism through TRH-mediated prolactin release 1, 3

Second-line hormonal assessment:

• LH and FSH (measured on cycle days 3-6) - Calculate LH/FSH ratio where >2 suggests PCOS, though less likely with elevated SHBG 2, 3
• Mid-luteal progesterone - Levels <6 nmol/L indicate anovulation 1
• Total testosterone - Levels >2.5 nmol/L suggest hyperandrogenism 2

Common Underlying Causes

Endocrine disorders:

• PCOS - Affects 4-6% of women and presents with irregular cycles, signs of androgen excess (hirsutism, acne, male-pattern hair distribution), and often elevated LH/FSH ratio 1, 2, 3
• Thyroid dysfunction - Both hypothyroidism and hyperthyroidism disrupt normal menstrual patterns through alterations in estrogen and progesterone hormone levels 1, 4
• Hyperprolactinemia - Causes anovulation and may present with galactorrhea or nipple discharge 1, 3
• Nonclassical congenital adrenal hyperplasia (NC 21-OHD) - Presents with hyperandrogenic signs including irregular periods, acne, frontal hair loss, and hirsutism; diagnosed definitively by CYP21A2 gene mutation analysis 5

Hypothalamic dysfunction:

• Stress, excessive exercise, or eating disorders - These cause functional hypothalamic amenorrhea by disrupting the hypothalamic-pituitary-ovarian axis 3, 6
• Significant weight changes - Both weight loss and gain can disrupt normal cycling 3

Structural/anatomic causes:

• Uterine fibroids, polyps, adenomyosis, or endometrial hyperplasia - Must be excluded, especially if bleeding persists despite hormonal normalization 7, 1, 8
• Endometriosis - Can present with irregular cycles and dysmenorrhea 1

Medication-related causes:

• Antiepileptic drugs (valproate, carbamazepine, phenytoin) - Can worsen menstrual irregularities and affect SHBG levels 1, 2
• Hormonal contraceptives - Progestin-only contraceptives, DMPA, and implants frequently induce irregular bleeding patterns 7

Imaging and Additional Workup

Pelvic ultrasound (transvaginal preferred) is indicated when:

• Hormonal tests suggest ovarian pathology 1, 2
• Evaluating for PCOS (>10 peripheral cysts of 2-8 mm diameter) 2, 3
• Excluding structural causes if bleeding persists despite treatment 7, 1

Treatment Algorithm Based on Etiology

For thyroid dysfunction:

• Initiate levothyroxine at 1.6 mcg/kg/day for patients without cardiac risk factors to normalize thyroid function 1
• Menstrual cycles typically normalize within 2-5 days of achieving adequate thyroid hormone replacement 1

For persistent irregular bleeding without identified pathology:

• First-line: NSAIDs such as mefenamic acid 500 mg three times daily for 5 days during bleeding episodes OR celecoxib 200 mg daily for 5 days 7, 1, 2
• Second-line: Tranexamic acid (contraindicated with active or history of thromboembolic disease) 1
• Third-line: Low-dose combined oral contraceptives (30-35 μg ethinyl estradiol) for 10-20 days if medically eligible, though this increases VTE risk 3-4 fold 1, 2, 3
• Long-term option: Levonorgestrel-releasing IUD reduces menstrual blood loss by 71-95% 1

For hypothalamic amenorrhea:

• Address underlying causes first (stress reduction, nutritional optimization, reducing excessive exercise) 3
• Optimize energy availability to >30 kcal/kg fat-free mass/day as first-line treatment 3

For ovulatory dysfunction with desire for pregnancy:

• Clomiphene citrate is indicated for treatment of ovulatory dysfunction in properly selected patients, including those with PCOS, after excluding impediments to pregnancy 8

Critical Pitfalls to Avoid

• Do not assume functional bleeding without excluding structural pathology, especially if irregularity persists beyond normal variation (cycles 21-45 days in young women) 3, 4
• Avoid aspirin as it may increase blood loss in women with baseline menstrual blood loss <60 mL 1
• Review all medications that may impact reproductive hormones before attributing irregularity to primary ovarian or hypothalamic causes 1, 2
• Do not use clomiphene citrate in patients with ovarian cysts (except PCOS), abnormal vaginal bleeding, or abnormal liver function 8

Referral Indications

Refer to endocrinology and/or gynecology when:

• Thyroid dysfunction is confirmed for specialized management 2
• Hormonal workup reveals complex endocrine abnormalities 2
• Bleeding persists despite two treatment attempts 1
• Infertility is a concern (inability to conceive after 12 months of unprotected intercourse) 2

Follow-Up Monitoring

• Reassess menstrual pattern within 1-2 cycles of initiating symptomatic bleeding management 1, 2
• Monitor TSH every 6-12 months once stable on thyroid replacement 1
• Evaluate patient satisfaction with contraceptive method if hormonal treatment initiated 2