What are the evidence‑based first‑line and second‑line treatment options for premenstrual syndrome in menstruating women?

Evidence-Based Treatment of Premenstrual Syndrome

First-Line Pharmacological Treatment

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for premenstrual syndrome when symptoms are moderate to severe and significantly impair functioning. 1, 2 These agents can be administered either continuously throughout the menstrual cycle or intermittently during the luteal phase only (typically starting 14 days before expected menses and continuing until menstruation begins), with both regimens demonstrating efficacy. 1, 2

SSRI Options and Dosing

• Fluoxetine, controlled-release paroxetine, and sertraline are FDA-approved specifically for premenstrual dysphoric disorder (PMDD), the severe form of PMS. 1
• These medications demonstrate excellent efficacy for both psychological symptoms (irritability, mood swings, depression, anxiety) and physical symptoms. 1, 3
• Luteal-phase-only dosing offers the advantage of reduced medication exposure and may improve adherence while maintaining therapeutic benefit. 1, 2

When SSRIs Are Most Appropriate

• Moderate to severe psychological symptoms (mood swings, irritability, depression, anxiety) that interfere with work, relationships, or daily activities. 4, 2
• Symptoms meeting criteria for PMDD (at least 5 symptoms including at least 1 core mood symptom, with marked functional impairment). 4, 2
• Failed response to lifestyle modifications and non-pharmacological interventions after 2-3 menstrual cycles. 2

First-Line Non-Pharmacological Treatment

All women with PMS should begin with lifestyle modifications and exercise as first-line recommendations, which may be sufficient for mild-to-moderate symptoms. 1

Dietary Modifications

• Eliminate xanthine-containing beverages (coffee, tea, cola, chocolate) from the diet, which can reduce nervousness, irritability, and breast tenderness. 5
• Implement luteal phase salt restriction (beginning approximately 7-10 days before expected menses) to reduce bloating and fluid retention. 5
• Ensure adequate protein and carbohydrate intake to support hormonal regulation. 6

Calcium Supplementation

• Calcium carbonate supplementation has demonstrated excellent efficacy for PMS symptom relief. 3
• This represents a simple, safe, and evidence-based intervention that should be recommended early in treatment. 2, 3

Exercise

• Regular physical activity should be maintained throughout the menstrual cycle. 6, 1
• Avoid overtraining, as excessive energy expenditure relative to intake can worsen menstrual dysfunction. 6

Second-Line Pharmacological Treatment

Combined Oral Contraceptives (COCs)

Combined oral contraceptives containing norgestimate are a second-line option when SSRIs are ineffective, contraindicated, or when contraception is also desired. 7, 4

• COCs with norgestimate have favorable side effect profiles according to ACOG. 7
• These agents are more effective for physical symptoms (breast tenderness, bloating, acne) than mood symptoms. 7
• Extended or continuous regimens (minimizing or eliminating placebo weeks) may provide better symptom control than standard 21-24 day hormone cycles. 7, 6
• Monophasic formulations are recommended for simplicity. 6
• Important caveat: COCs carry approximately 3-4 times increased baseline risk of venous thromboembolism. 7

When to Consider COCs

• Predominant physical symptoms (breast tenderness, bloating, acne) rather than mood symptoms. 7
• Patient desires contraception in addition to PMS treatment. 4, 1
• SSRIs are contraindicated, not tolerated, or ineffective after adequate trial. 4, 1

Symptom-Specific Adjunctive Treatments

For Physical Symptoms

NSAIDs (ibuprofen 400 mg every 4-6 hours or naproxen 440-550 mg every 12 hours) for 5-7 days during the luteal phase can effectively manage breast tenderness, cramping, headache, and joint pain. 7, 6, 1

• Mefenamic acid has shown efficacy in small studies and can be used as an alternative NSAID. 7, 6
• These should be taken with food and limited to short-term use during symptomatic days. 6
• NSAIDs can be used as monotherapy for mild PMS with predominantly physical symptoms or as adjunctive therapy with SSRIs or COCs. 1

For Fluid Retention and Bloating

Spironolactone can be used as supportive care for bloating and fluid retention when dietary salt restriction is insufficient. 1, 5

• Typically administered during the luteal phase only. 5
• Mild diuretics may be added if necessary during the last week before menses. 5

For Anxiety Symptoms

Anxiolytics may be used as supportive care for severe anxiety symptoms, though they are not first-line agents. 1

Alternative and Hormonal Therapies

GnRH Agonists

Gonadotropin-releasing hormone (GnRH) agonists represent a third-line option for severe, refractory PMDD when SSRIs and hormonal contraceptives have failed. 4, 1

• These agents suppress ovulation completely, eliminating hormonal fluctuations. 4, 1
• Significant adverse effects (menopausal symptoms, bone density loss) limit their use. 1
• Should only be considered under specialist supervision for the most severe cases. 4

Non-Contraceptive Estrogen Formulations

Non-contraceptive estrogen formulations may be used in select cases of severe PMDD, but require specialist management. 4

Treatment Algorithm

1. Initial approach (all patients):

   • Confirm diagnosis with prospective daily symptom calendar for 2-3 menstrual cycles. 2, 3
   • Eliminate xanthine-containing beverages. 5
   • Implement luteal phase salt restriction. 5
   • Recommend calcium carbonate supplementation. 2, 3
   • Encourage regular exercise. 1

2. If symptoms persist after 2-3 cycles (moderate to severe symptoms):

   • For predominant mood symptoms: Initiate SSRI (fluoxetine, sertraline, or controlled-release paroxetine), either continuous or luteal-phase dosing. 1, 2
   • For predominant physical symptoms or when contraception desired: Consider COC with norgestimate, preferably extended/continuous regimen. 7, 4

3. Adjunctive symptom-specific therapy (as needed):

   • NSAIDs for pain, cramping, headache. 7, 6, 1
   • Spironolactone for persistent bloating. 1, 5

4. If first-line pharmacotherapy fails:

   • Switch between SSRI and COC if one class ineffective. 4, 1
   • Consider combination therapy (SSRI + symptom-specific agents). 1

5. Refractory cases:

   • Refer to gynecology or psychiatry specialist. 4
   • Consider GnRH agonists under specialist supervision. 4, 1

Critical Pitfalls to Avoid

• Do not prescribe COCs as first-line for predominant mood symptoms – SSRIs are significantly more effective for psychological symptoms. 7, 1
• Do not rely on standard 21/7 COC regimens – extended or continuous regimens provide superior symptom control by minimizing hormone-free intervals. 7, 6
• Do not recommend herbal remedies or vitamin D as primary therapy – insufficient evidence exists to support these interventions despite their popularity. 2
• Do not diagnose PMS without prospective symptom tracking – retrospective recall is unreliable and may lead to misdiagnosis of other psychiatric or medical conditions. 2, 3
• Do not continue ineffective therapy beyond 2-3 menstrual cycles – if no improvement occurs, escalate treatment rather than prolonging an inadequate regimen. 6, 2

Evidence Quality Considerations

The strongest evidence supports SSRIs as first-line pharmacotherapy, with multiple controlled trials demonstrating efficacy and FDA approval for this indication. 1, 2 Evidence for COCs is more limited, with the norgestimate formulation having the best safety profile according to ACOG guidelines. 7 Calcium supplementation has demonstrated excellent efficacy in controlled trials. 3 Evidence for herbal supplements, acupuncture, and vitamin D remains insufficient or conflicting, and these should not be recommended as primary therapy. 2